PTH1r agonist compound, pharmaceutical composition and use thereof

Abstract

Provided in the present invention is a compound of formula (I), which compound exhibits good PTH1R agonistic activity and can be used in the treatment of PTH1R-related diseases. The compound of the present invention exhibits not only good levels of biological activity and safety, but also exhibits improved transmembrane activity and drug bioavailability.

Description

PTH1R agonist compounds, pharmaceutical compositions, and uses thereof

[0001] This application claims priority to:

[0002] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on September 26, 2024, with the patent application number 202411353981.8;

[0003] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on October 22, 2024, with the patent application number 202411479160.9;

[0004] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on November 12, 2024, with the patent application number 202411611948.0;

[0005] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on December 17, 2024, with the patent application number 202411863992.0;

[0006] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on January 10, 2025, with the patent application number 202510044743.7;

[0007] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on January 24, 2025, with the patent application number 202510120728.6;

[0008] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on February 27, 2025, with the patent application number 202510227790.5;

[0009] A prior application entitled “PTH1R agonist compounds, pharmaceutical compositions, and uses thereof” filed with the China National Intellectual Property Office on March 28, 2025, with the patent application number 202510386300.6;

[0010] The priority of the prior application with the patent application number 202510428256.0 and the name of "PTH1R agonist compound, pharmaceutical composition and application thereof" filed on April 7, 2025 to the China National Intellectual Property Bureau;

[0011] The priority of the prior application with the patent application number 202510652798.6 and the name of "PTH1R agonist compound, pharmaceutical composition and application thereof" filed on May 20, 2025 to the China National Intellectual Property Bureau;

[0012] The prior application is incorporated by reference in the present application. TECHNICAL FIELD

[0013] The present application belongs to the field of pharmaceutical compounds, and specifically relates to PTH1R agonist compounds, pharmaceutical compositions and application thereof. BACKGROUND

[0014] Parathyroid hormone (PTH) is a polypeptide composed of 84 amino acids, which is mainly responsible for the regulation of calcium and phosphorus homeostasis in the body and bone metabolism, and is secreted by the parathyroid gland. In the kidney, PTH increases the reabsorption of calcium in the distal convoluted tubule and inhibits the reabsorption of phosphorus in the proximal convoluted tubule, thereby playing a role in calcium retention and phosphorus excretion. On the other hand, PTH promotes the production of active vitamin D, calcitriol, and increases the absorption of calcium in the small intestine. In the bone, a sustained and stable level of PTH can promote the differentiation of osteoclasts and release calcium from the bone through bone resorption, while a pulsed level of PTH can promote bone formation. The homologous analog of PTH, parathyroid hormone-related protein (PTHrP), also has similar biological effects. This class of proteins is not secreted by the parathyroid gland, but is produced by various tissue cells including bone, kidney, mammary gland, skin, etc., and acts in a paracrine, autocrine and intracellular manner.

[0015] PTH and PTHrP regulate serum calcium levels by activating parathyroid hormone type 1 receptor (PTH1R). PTH1R belongs to the G protein-coupled receptor B family, which is widely expressed in the body, and recognizes PTH and PTHrP (PTH-related peptide) and their active truncated polypeptides, PTH(1-34) and PTHrP(1-36). After binding to the ligand, PTH1R / PTHrP stabilizes the active conformation of PTH1R, promotes the coupling and activation of G protein heterotrimer, and mainly plays a role in target organs such as bone and kidney through the Gs / adenylyl cyclase / PKA pathway. There are two activation modes of PTH1R, one of which is the RG conformation, mainly responsible for transient cAMP production, which can be induced by both PTH and PTHrP; the other is called R0 conformation, which can only be induced by PTH binding. The affinity of R0 conformation is independent of G protein coupling, and after receptor internalization, it can still maintain long-term Gs protein activation and continuous production of cAMP.

[0016] The osteogenic effect of PTH has been successfully translated in the clinic. Teriparatide PTH(1-34) developed by Eli Lilly and Abaloparatide PTHrP(1-34) developed by Radius are used for osteoporosis, and Tran-PTH developed by Wison Pharmaceutical has been approved in the European Union for the treatment of hypoparathyroidism (HP). In the treatment of osteoporosis, unlike other drugs with bone resorption inhibition as the pharmacological mechanism, human recombinant PTH teriparatide and abaloparatide can not only significantly increase bone density, but also have bone anabolism, which can promote bone repair and maintain the structure and strength of the skeleton. Hypoparathyroidism is an endocrine disease caused by insufficient secretion or insufficient receptor response of PTH, characterized by hypocalcemia and hyperphosphatemia, which seriously affects the quality of life. Compared with traditional calcium supplementation, PTH replacement therapy such as teriparatide can more significantly relieve the blood, kidney, bone and neurological symptoms of HP, and does not cause increased urinary calcium, avoiding kidney damage due to kidney calcium deposition. However, the approved PTH peptide drugs have a short half-life and poor oral availability, and need to be injected daily, and long-term use has a risk of osteosarcoma, which has application limitations in the clinic. The development of oral agonists can provide more possibilities for patients with osteoporosis and hypoparathyroidism in the future. SUMMARY

[0017] The small molecule compound disclosed in the application can target PTH1R, simulate PTH to activate the function of PTH1R, regulate the bone synthesis and decomposition metabolism of the body, restore the calcium and phosphorus homeostasis, and is used for treating osteoporosis or HP through oral administration. Compared with the peptide replacement therapy, the production cost is lower, and the administration is more convenient and comfortable.

[0018] The application provides a compound shown in formula (I), a racemate, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug compound thereof.

[0019] Z is selected from O or S;

[0020] Q is selected from N or CR q ; R q is selected from H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano C 1-6 alkylene, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;

[0021] ring D is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R d ; each R d is the same or different and independently selected from H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or two adjacent R d together with the atoms to which they are each attached form a C 4-10 cycloalkenyl ring;

[0022] ring F is selected from wherein 1 and 2 are fused to the left heteroaromatic ring and 3 is connected to the right ;

[0023] Y is selected from N or CR5; wherein R5 is selected from H, CN, OH, halogen, C c alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 2-10 alkynyl or C 3-6 cycloalkyl; each R c is the same or different and independently selected from CN, OH, halogen or C 1-6 alkyl; or, R5 is connected to R through L (-R5'-L-R'-) to form a macrocyclic compound, wherein R5' is selected from -O- or a direct bond; L is selected from C 3-20 Alkylene or C 3-20 alkenyl group; R' is selected from -NH-;

[0024] R3 is selected from halogenated C 1-6 alkyl;

[0025] R4 is selected from OH or NH2;

[0026] Alternatively, R3, R4, and the carbon atom they are bonded to form C. 3-6 cycloalkyl ring;

[0027] R is selected from -NR1R2, C 1-6 Alkyl groups or unsubstituted or optionally substituted with one, two or more R groups r The following groups are substituted: benzene ring, 5-6 membered heteroaromatic ring; each R r They may be the same or different, and are independently selected from H, OH, CN, halogens, or C. 1-6 alkyl;

[0028] R1 and R2 may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more Rs. a The following groups are substituted: C 1-10 Alkyl, Cyclic A, -NR a1 R a2 C 1-10 Alkoxy, -R a3 - Ring A; Ring A is selected from C 3-10 Cycloalkyl groups, containing one or more 3-10 membered heterocyclic groups selected from N, O, and S heteroatoms; each R a Same or different, selected independently from C 1-10 Alkyl, Halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1- 10 Alkyl-NH-, (C 1-10 alkyl)2-N-, -S(=O)(=NH)C 1-10 alkyl, =NOC 1-6 Alkyl, cyano C 1-10 Alkyl group, -NHS(=O)2C 1-10 Alkyl or C 2-10 Alkyne group; R6 and R7 may be the same or different, and are independently selected from H, halogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -C(=O)R a4 ;R a1 and R a2 Whether the two are the same or different, they are selected independently from H and C. 1-6alkyl; R a3 selected from C 1-6 alkylene; R a4 selected from hydroxyl or C 1-10 alkoxy;

[0029] or, R1and R2, together with the atoms to which they are attached, form a ring B which is unsubstituted or optionally substituted by one, two or more R b substituents; each R b is the same or different, independently of each other, selected from OH, C 1-10 alkyl, haloC 1-10 alkyl, C 1-10 alkyl-NH-, (C 1-10 alkyl)2-N-, -NH-S(=0)2-C 1-10 alkyl, -S(=0)2-C 1-10 alkyl, (C 1-10 alkyl)2-N-C(=0)-, C 1-10 alkoxy-C(=0)-, cyanoC 1-10 alkyl, C 1-10 alkoxy, haloC 1-6 alkoxy, R6, R7are the same or different, independently of each other, selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, -C(=0)R a4 ; R a4 selected from hydroxyl or C 1-10 alkoxy;

[0030] R8is selected from H, CN or halogen; or, R8, R5, together with the carbon atoms to which each is attached, form a C 4-8 carbocyclic ring or 4-8 membered heterocyclic ring.

[0031] According to an embodiment of the present application, Z is selected from O.

[0032] According to an embodiment of the present application, Z is selected from S.

[0033] ring D is selected from the following groups, which are unsubstituted or optionally substituted by one, two or more R d substituents; each R d is the same or different, independently of each other, selected from H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl or two adjacent R d together with the atoms to which each is attached, form a C 4-6 cycloalkenyl ring;

[0034] According to embodiments of the present application, ring D is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R d substituted phenyl ring, 5-6 membered heteroaromatic ring; each R d are the same or different, independently of each other, selected from H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl.

[0035] According to embodiments of the present application, ring D is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R d substituted phenyl ring, thiophene ring (e.g. ), thiazole ring (e.g. ), pyridine ring, pyrimidine ring (e.g. ), pyrazole ring (e.g. );

[0036] According to embodiments of the present application, ring D is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R d substituted phenyl ring, thiophene ring (e.g. ) or thiazole ring (e.g. ).

[0037] According to embodiments of the present application, each R d are the same or different, independently of each other, selected from H, F, Cl, Br, CN, methoxy, methyl, or adjacent two R d together with the atoms to which they are each attached form a C 4-6 cycloalkenyl ring.

[0038] According to embodiments of the present application, each R d are the same or different, independently of each other, selected from H, F, or adjacent two R d together with the atoms to which they are each attached form

[0039] According to embodiments of the present application, each R d are the same or different, independently of each other, selected from H, F, Cl, Br, CN, methoxy or methyl.

[0040] According to embodiments of the present application, ring D is selected from

[0041] According to embodiments of the present application, ring D is selected from

[0042] According to embodiments of the present application, ring D is selected from

[0043] According to an embodiment of the present application, Q is selected from N.

[0044] According to an embodiment of the present application, Q is selected from CR q ; R q is selected from H, OH, CN, halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano C 1-3 alkylene, halo C 1-3 alkyl or halo C 1-3 alkoxy.

[0045] According to an embodiment of the present application, R q is selected from H, CN, F, Cl, Br, methyl, trifluoromethyl, cyanomethylene, 2,2,2-trifluoroethyl or -OF2Cl.

[0046] According to an embodiment of the present application, Y is selected from N.

[0047] According to an embodiment of the present application, Y is selected from CR5, wherein R5is selected from H, CN, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1- 6alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl.

[0048] According to an embodiment of the present application, R5is selected from H, CN, OH, F, Cl, Br, methyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, cyclopropyl or 1-propynyl.

[0049] According to an embodiment of the present application, R5is linked to R via L (-R5'-L-R'-) to form a macrocyclic compound, wherein R5' is selected from -O-, L is selected from C 3-20 alkylene; R' is selected from -NH-; preferably, L is selected from -CH2-CH=CH-(CH2)4-.

[0050] According to an embodiment of the present application, R3is selected from fluoro C 1-3 alkyl.

[0051] According to an embodiment of the present application, R3is selected from trifluoromethyl or difluoromethyl.

[0052] According to an embodiment of the present application, R4is selected from OH or NH2.

[0053] According to an embodiment of the present application, R3, R4and the carbon atom to which they are jointly attached form a cyclobutane ring.

[0054] According to an embodiment of the present application, R is selected from -NR1R2, C 1-6 alkyl, or unsubstituted or optionally substituted by one, two or more R r substituted phenyl or 5-6 membered nitrogen containing heteroaryl; each R r are the same or different and independently from each other selected from H, CN or C 1-6 alkyl.

[0055] According to an embodiment of the present application, R is selected from C 1-6 alkyl, or unsubstituted or optionally substituted by one, two or more R r substituted pyrazolyl, imidazolyl, thiazolyl or pyridyl.

[0056] According to an embodiment of the present application, R is selected from unsubstituted or optionally substituted by one, two or more R r substituted phenyl,

[0057] According to an embodiment of the present application, each R r are the same or different and independently from each other selected from H, CN or methyl.

[0058] According to an embodiment of the present application, R is selected from C 1-3 alkyl, preferably R is selected from ethoxy.

[0059] According to an embodiment of the present application, R is selected from ethoxy;

[0060] According to an embodiment of the present application, R is selected from -NR1R2, wherein R1and R2are the same or different and independently from each other selected from H, unsubstituted or optionally substituted by one, two or more R a substituted C 1-6 alkyl, ring A, -NR a1 R a2 , C 1-6 alkyl, -R a3 -ring A; said ring A is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl containing one N heteroatom; R a , R a1 , R a2 , R a3 have the definitions as described hereinbefore;

[0061] According to an embodiment of the present application, each R a are the same or different and independently from each other selected from C1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=O)(=NH)C 1-6 alkyl, cyanoC 1-6 alkyl, -NHS(=O)2C 1-6 alkyl, haloC 1-6 alkoxy or C 2-6 alkynyl.

[0062] According to an embodiment of the present application, R1and R2are identical or different, independently from each other, selected from H, unsubstituted or optionally substituted by one, two or more R a substituted following groups: C 1-10 alkyl, ring A; the ring A is selected from C 3-10 cycloalkyl; each R a is identical or different, independently from each other, selected from C 1-10 alkyl, haloC 1-10 alkyl, C 1-10 alkyl-NH-, (C 1-10 alkyl)2-N-, -S(=O)(=NH)C 1-10 alkyl, R6, R7are identical or different, independently from each other, selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl;

[0063] or R1and R2form, with the atoms to which they are attached, an unsubstituted or optionally substituted ring B selected from 4-10 membered heterocyclyl; each R b is identical or different, independently from each other, selected from OH, C b alkyl, haloC 1-10 alkyl, C 1-10 alkyl, C 1-10 alkyl-NH-, (C 1-10 alkyl)2-N-, -NH-S(=O)2-C 1-10 alkyl, -S(=O)2-C 1-10 alkyl, (C 1-10 alkyl)2-N-C(=O)-, C 1-10 alkoxy-C(=O)-, R6, R7are identical or different, independently from each other, selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6alkyl;

[0064] According to an embodiment of the present application, R1and R2are the same or different, independently of one another, selected from H, the following groups, which are unsubstituted or optionally substituted by one, two or more R a substituted following groups: C 1-6 alkyl, ring A, -NR a1 R a2 , C 1-6 alkoxy, -R a3 ring A; the ring A is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl containing one N heteroatom.

[0065] According to an embodiment of the present application, R1and R2are the same or different, independently of one another, selected from H, the following groups, which are unsubstituted or optionally substituted by one, two or more R a substituted following groups: C 1-6 alkyl, ring A; the ring A is selected from C 3-6 cycloalkyl.

[0066] According to an embodiment of the present application, R1and R2are the same or different, independently of one another, selected from H, the following groups, which are unsubstituted or optionally substituted by one, two or more R a substituted following groups: methyl, ethyl or methoxy.

[0067] According to an embodiment of the present application, R1and R2are the same or different, independently of one another, selected from H, the following groups, which are unsubstituted or optionally substituted by one, two or more R a substituted following groups: methyl, ethyl.

[0068] According to an embodiment of the present application, ring A is selected from cyclobutyl, cyclopentyl, azetidinyl (e.g. ).

[0069] According to an embodiment of the present application, ring A is selected from cyclobutyl or cyclopentyl.

[0070] According to an embodiment of the present application, each R a is the same or different, independently of one another, selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=O)(=NH)C 1-6 alkyl, cyanoC 1-6 alkyl, -NHS(=O)2C 1-6 alkyl.

[0071] According to an embodiment of the present application, each R a is the same or different, independently of one another, selected from C1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=O)(=NH)C 1-6 alkyl, R6 and R7 may be the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 alkyl.

[0072] According to an embodiment of the present invention, R6 and R7 may be the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl group, -COOH, -C(=O)C 1-3 Alkyl group.

[0073] According to an embodiment of the present invention, R6 and R7 may be the same or different, and are independently selected from H, halogens, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl group, -COOH.

[0074] According to embodiments of the present invention, R6 and R7 may be the same or different, and are independently selected from H, F, Cl, Br, methyl, hydroxymethyl, trifluoromethyl, and -COOH.

[0075] According to an embodiment of the present invention, R6 is selected from halogens or H, and R7 is selected from H, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl group, -COOH, -C(=O)C 1-3 Alkyl group.

[0076] According to an embodiment of the present invention, R6 is selected from halogens, and R7 is selected from H, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl group, -COOH.

[0077] According to an embodiment of the present invention, Selected from

[0078] According to an embodiment of the present invention, R6 and R7 may be the same or different, and are independently selected from H, halogens, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 alkyl.

[0079] According to an embodiment of the present application, R6, R7are the same or different, independently of one another selected from H, F, CI, Br, methyl, hydroxymethyl, trifluoromethyl.

[0080] According to an embodiment of the present application, R6is selected from halogen or H, R7is selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl.

[0081] According to an embodiment of the present application, R6is selected from halogen, R7is selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl.

[0082] According to an embodiment of the present application, is selected from

[0083] According to an embodiment of the present application, each R a are the same or different, independently of one another selected from C 1-6 alkylene, haloC 1-6 alkylene, hydroxy-haloC 1-6 alkylene, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=0)(=NH)C 1-6 alkyl, cyanoC 1-6 alkyl, -NHS(=0)2C 1-6 alkyl, HOOC-haloC 1-6 alkylene, =N-O-C 1-6 alkyl, haloC 2-6 alkenyl, haloC 1-6 alkoxy or C 2-6 alkynyl.

[0084] According to an embodiment of the present application, each R a are the same or different, independently of one another selected from C 1-6 alkylene, haloC 1-6 alkylene, hydroxy-haloC 1-6 alkylene, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=0)(=NH)C 1-6 alkyl, cyanoC 1-6 alkyl, -NHS(=0)2C 1-6 alkyl or HOOC-haloC 1-6Alkylene.

[0085] According to an embodiment of the present invention, each R a Same or different, selected independently from C 1-6 Alkylene, Halogenated C 1-6 Alkylene, hydroxyl-halogenated C 1-6 Alkylene, C 1-6 Alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=O)(=NH)C 1-6 alkyl.

[0086] According to an embodiment of the present invention, each R a They may be the same or different, and are independently selected from methylamino, dimethylamino, Ethynyl, 1-propynyl, difluoromethoxy, or trifluoromethoxy.

[0087] According to an embodiment of the present invention, each R a They may be the same or different, and are independently selected from methylamino, dimethylamino,

[0088] According to an embodiment of the present invention, each R a They may be the same or different, and are independently selected from methylamino, dimethylamino,

[0089] According to embodiments of the invention, R1 and R2 form unsubstituted or optionally substituted atoms with one, two or more R atoms. b The substituted ring B is selected from 4-9 member nitrogen-containing heterocyclic groups.

[0090] According to an embodiment of the present invention, ring B is selected from...

[0091] According to an embodiment of the present invention, each R b They are either the same or different, and are independently selected from OH and C. 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, (C 1-6 alkyl)2-NC(=O)-, C 1-6 Alkoxy-C(=O)-, Cyano C1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy; R6, R7 independently of one another have the definitions indicated above.

[0092] According to an embodiment of the application, each R b are identical or different, independently of one another selected from OH, C 1-6 alkyl, C 1-6 alkylene, halogen-C 1-6 alkylene, hydroxy-halogen-C 1-6 alkylene, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, -NH-S(=0)2-C 1-6 alkyl, -S(=0)2-C 1-6 alkyl, (C 1-6 alkyl)2-N-C(=0)-, C 1-6 alkoxy-C(=0)-, cyano-C 1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy.

[0093] According to an embodiment of the application, each R b are identical or different, independently of one another selected from OH, methyl, methylamino, dimethylamino,

[0094] According to an embodiment of the application, each R b are identical or different, independently of one another selected from OH, C 1-10 alkyl, halogen-C 1-10 alkyl, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, -NH-S(=0)2-C 1-6 alkyl, -S(=0)2-C 1-6 alkyl, (C 1-6 alkyl)2-N-C(=0)-, C 1-6 alkoxy-C(=0)-, R6, R7 independently of one another have the definitions indicated above.

[0095] According to an embodiment of the application, each R b are identical or different, independently of one another selected from OH, C 1-6 alkyl, C 1-6 alkylene, halogen-C 1-6 alkylene, hydroxy-halogen-C 1-6 alkylene, C 1-6 alkyl-NH-, (C1-6 Alkyl)2-N-, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, (C 1-6 alkyl)2-NC(=O)-, C 1-6 Alkoxy-C(=O)-.

[0096] According to an embodiment of the present invention, each R b They may be the same or different, and are independently selected from OH, methyl, methylamino, dimethylamino, etc.

[0097] According to an embodiment of the present invention, R a1 and R a2 They are the same or different, and are selected independently from H or C. 1-3 alkyl.

[0098] According to an embodiment of the present invention, R a1 and R a2 They may be the same or different, and are independently selected from H or ethyl.

[0099] According to an embodiment of the present invention, R a3 Selected from C 1-3 Alkylene.

[0100] According to an embodiment of the present invention, R a3 Selected from methylene.

[0101] According to an embodiment of the present invention, R a4 Selected from hydroxyl or C 1-6 Alkyl group.

[0102] According to an embodiment of the present invention, R a4 Selected from hydroxyl groups.

[0103] According to an embodiment of the present invention, Selected from

[0104] According to an embodiment of the present invention, Selected from

[0105] According to an embodiment of the present invention, R8 is selected from H.

[0106] According to an embodiment of the present invention, R8 and R5, together with their respective bonded carbon atoms, form C. 4-8 Carbon rings or 4-8 membered heterocycles; the condition is... at least one substituent wherein R6, R7have the definitions described herein.

[0107] According to an embodiment of the present application, R8, R5, together with the carbon atom to which each is attached, form a C 4-6 cycloalkenyl ring or 4-6 membered heterocyclic ring.

[0108] According to an embodiment of the present application, R8, R5, together with the carbon atom to which each is attached, form a 3-6 membered heterocyclyl ring containing one O heteroatom;

[0109] According to an embodiment of the present application, R8, R5, together with the carbon atom to which each is attached, form a

[0110] According to an embodiment of the present application, the compound of formula (I) is selected from the following structures:

[0111] wherein ring D, Z, Y, R, R1, R2, R3, R4, R8, R q each independently have the definitions described herein.

[0112] According to an embodiment of the present application, the compound of formula (I) is selected from the following structures:

[0113] wherein ring D, ring F, Z, Q, Y, R1, R3, R4, R6, R7, R8 each independently have the definitions described herein;

[0114] E is selected from C 1-6 alkylene;

[0115] Alternatively, E is selected from a ring A which is unsubstituted or optionally substituted with one, two or more R a substituted ring A;

[0116] Alternatively, R1and E form, with the atom to which each is attached, a ring B which is unsubstituted or optionally substituted with one, two or more R b substituted ring B;

[0117] said ring A, ring B, R a , R b each independently have the definitions described herein;

[0118] Preferably, E is selected from a cyclobutane ring, or R1and E form, with the nitrogen atom to which each is attached, a nitrogen-containing cyclobutane.

[0119] According to an embodiment of the present application, the compound of formula (I) is selected from the following structures:

[0120] wherein ring A, ring B, Y, R1, R8, R a , R b , R d each independently have the definitions described above; m, n, p are the same or different, and each independently selected from 0, 1, 2, 3, 4 or 5.

[0121] According to an embodiment of the present application, the compound of formula (I) is selected from the following structures:

[0122] wherein ring D, ring F, Z, Q, R3, R4, R6, R7 each independently have the definitions described above.

[0123] According to an embodiment of the present application, the compound of formula (I) is selected from the following compounds:

[0124] The present application also provides a method for preparing a compound of formula (IA-1), comprising the following step: reacting compound a and compound b to obtain a compound of formula (IA-1);

[0125] wherein Z, ring D, Y, R1, R2, R3, R4, R8 each independently have the definitions described above; X is selected from a leaving group, such as OH, halogen.

[0126] According to an embodiment of the present application, the reaction can be carried out in the presence of a solvent, such as an organic solvent or a mixed solvent of an organic solvent and water. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenyl ethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl glycol dimethyl ether, diphenyl ether, propyl ether, isopropyl ether, isobutyl ether, isoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and hydrocarbons that can be substituted with fluorine and / or chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, acetone, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0127] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof.

[0128] According to some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0129] According to some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0130] The present application also provides a method for preventing and / or treating a PTH1R-mediated disease or disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, alone.

[0131] The present application also provides a method of treating or preventing a PTH1R-mediated disease or disorder, comprising administering to a patient a prophylactically or therapeutically effective amount of the above pharmaceutical composition.

[0132] According to some embodiments, the PTH1R-mediated disease or disorder is selected from hypoparathyroidism and / or osteoporosis.

[0133] According to some embodiments, the PTH1R-mediated disease or disorder is selected from osteoporosis, bone fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcinosis.

[0134] According to some embodiments, the patient comprises a mammal, preferably a human.

[0135] The present application also provides at least one of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a PTH1R-mediated disease or disorder.

[0136] According to some embodiments, the PTH1R-mediated disease or disorder is selected from osteoporosis, bone fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcinosis.

[0137] The present application also provides the use of at least one of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, for the manufacture of a medicament.

[0138] According to some embodiments, the use can be a use in the manufacture of a medicament for PTH1R agonism.

[0139] According to some embodiments, the use can be a use in the manufacture of a medicament for treating or preventing hypoparathyroidism and / or osteoporosis.

[0140] According to some embodiments, the use can be a use in the manufacture of a medicament for treating or preventing osteoporosis, bone fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcinosis. Beneficial effects

[0141] The compounds provided by the present application have good PTH1R agonistic activity, and can be used for the treatment of diseases related to PTH1R. The compounds of the present application not only have good biological activity and good safety, but also improve the transmembrane activity and drug bioavailability.

[0142] Definitions of terms and explanations

[0143] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims hereof, including definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other in any manner. The group definitions and compound structures after such combination should be understood to be within the scope recited in the specification and / or claims.

[0144] Unless otherwise indicated, the numerical ranges recited in the specification and claims hereof are equivalent to reciting each and every integer value within the range. For example, a numerical range of "1-10" is equivalent to reciting each and every integer value within the range of "1-10", i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0145] It should be understood that herein in describing one, two or more, "more" should mean greater than 2, for example an integer greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0146] The term "carbocyclo" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[l. l. l]pentane ring, bicyclo[2.2. l]heptane ring, bicyclo[3.2. l]octane ring or bicyclo[5.2.0]nonane ring, decahydronaphthalene ring, and the like), which can be optionally substituted with 1 or more (such as 1, 2, or 3) suitable substituents. The term "3-6 membered carbocyclo" refers to a carbocyclo ring containing 3, 4, 5, or 6 ring-forming carbon atoms.

[0147] The term "halogen" denotes fluorine, chlorine, bromine and iodine.

[0148] The term "C 1-10 "alkyl" is to be understood as meaning a straight-chain or branched saturated monovalent hydrocarbon group having from 1 to 10 carbon atoms. For example, "C 1-8 "alkyl" denotes straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 "alkyl" denotes straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like or isomers thereof.

[0149] The term "C 2-20 "alkenyl" is to be understood as meaning a straight-chain or branched monovalent hydrocarbon group which contains one or more double bonds and which has from 2 to 20 carbon atoms, preferably "C 2-10 "alkenyl". "C 2-10 "alkenyl" is to be understood as preferably meaning a straight-chain or branched monovalent hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 "alkenyl" which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 "alkenyl" with 2 or 3 carbon atoms (i.e., C 2-3alkenyl). It is to be understood that in case the alkenyl group comprises more than one double bond, the double bonds can be isolated from one another or conjugated. The alkenyl group is, for example, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l-enyl, (Z)-pent-l-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-l-enyl, (Z)-hex-l-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l-enyl, (Z)-l-methylprop-l-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-l-methylbut-2-enyl, (Z)-l-methylbut-2-enyl, (E)-3-methylbut-l-enyl, (Z)-3-methylbut-l-enyl, (E)-2-methylbut-l-enyl, (Z)-2-methylbut-l-enyl, (E)-l-methylbut-l-enyl, (Z)-l-methylbut-l-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-l-enyl, 1-propylvinyl, 1-isopropylvinyl. The term alkenylene is to be understood as the divalent form of an alkenyl group.

[0150] The term "alkenylene" denotes the residue derived from removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkenyl group, wherein alkenyl is as defined above.

[0151] The term "alkynyl" refers to a straight-chain or branched one-, two- or more triple-bonded, monovalent unsaturated aliphatic hydrocarbon radical. The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0152] The term "C 3-10 Cycloalkyl" is understood to mean a saturated, monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably "C 3-8 Cycloalkyl", more preferably "C 3-6 Cycloalkyl". The term "C 3-6 Cycloalkyl" is understood to mean a saturated, monovalent monocyclic, bicyclic (e.g. bridged, spirocyclic) or tricyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. The C 3-10 Cycloalkyl" is understood to mean a saturated, monovalent monocyclic, bicyclic (e.g. bridged, spirocyclic) or tricyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. The C

[0153] The term "C 3-12"Cycloalkenyl" is understood to mean a monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic alkene containing a carbon-carbon double bond having 3 to 12 carbon atoms, preferably "C 3-10 "Cycloalkenyl", more preferably "C 3-8 "Cycloalkenyl", which can have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Said C 3-12 "Cycloalkenyl" can be a monocyclic alkyl group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenenyl or cyclodecenyl, or a bicyclic alkyl group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.

[0154] The term "3-10 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g. which is a 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9- or 10-membered bicyclic (e.g. fused, bridged, spirocyclic) ring system and contains at least one, e.g. 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S can also optionally be oxidized into various oxidation states to form a nitro oxide, -S(O)- or -S(O)2- state. Preferably, the heterocyclyl group can be selected from "3-6 membered heterocyclyl". The term "3-6 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclyl group can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring, such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e. it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.

[0155] The term "spirocyclic" refers to a ring system in which two rings share 1 atom that is part of the ring.

[0156] The term "fused ring" refers to a ring system in which two rings share 2 ring-forming atoms.

[0157] The term "bridged ring" refers to a ring system in which two rings share 3 or more ring-forming atoms.

[0158] "Haloalkyl" means an alkyl group, as defined above, substituted by one or more halogens.

[0159] The term "oxo" refers to an oxygen group substituted (=0) formed by oxidation of a carbon atom, nitrogen atom or sulfur atom in a substituent.

[0160] The term "macrocyclic compound" refers to an organic molecule comprising a macrocyclic structure with more than 10 ring atoms.

[0161] In the chemical structures of the compounds according to the present application, the bond indicates unspecified configuration, indicates absolute configuration, i.e. if stereoisomers are present in the chemical structure, the bond may be or both configurations.

[0162] In the present application, the compounds referred to also include isotopically-labeled compounds, which are identical to those recited in Formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into a compound of the application include isotopes of H, C, N, O, S, F, and CI, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present application, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the above isotopes and / or other isotopes of other atoms are within the scope of this application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H), and carbon-14, i.e., 14 C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 ​H or D) substitutions can provide certain therapeutic advantages resulting from, for example, increased metabolic stability or decreased dosing requirements, and can therefore be preferred in certain situations. The presence of hydrogen in the substituents of the present application does not represent exclusion of deuterium or tritium, but rather deuterium or tritium can also be contained, if appropriate.

[0163] It will be appreciated by those skilled in the art that the compounds of formula (I) can exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (for example, a carboxyl group) and a basic center (for example, an amino group), they can also form inner salts.

[0164] The compounds of the present application can exist in the form of solvates (such as hydrates), wherein the compound of the present application contains a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0165] Depending on their molecular structure, the compounds of the present application can be chiral and thus can exist in various enantiomeric forms. The compounds can thus exist in racemic or optically active form. The compounds of the present application encompass the isomers with R or S configuration at each chiral carbon or mixtures thereof, racemates. The compounds of the present application or intermediates thereof can be separated into the enantiomeric compounds by chemical or physical methods known to those skilled in the art or used in the synthesis. In the case of racemic amines, the diastereomeric isomers are prepared from the mixture by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids, such as, for example, the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids, for example, N-benzoylproline or N-benzenesulfonylproline, or various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography can also be advantageously carried out with optically active stationary phases, for example, dinitrobenzoylphenylglycine, cellulose trisporate or other carbohydrate derivatives or chiral derivatized isobutyryl ester polymers, fixed on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0166] The corresponding stable isomers can be separated according to known methods, for example, by extraction, filtration or column chromatography.

[0167] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0168] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder, or condition from occurring in an individual that is predisposed or susceptible to the disease, disorder, and condition but has not yet been experienced or displayed the pathology or symptoms of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder, or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder, or condition (i.e., retarding the further development of the pathology and / or symptoms); (3) relieving the disease: for example, relieving a disease, disorder, or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder, or condition (i.e., reversing the pathology and / or symptoms).

[0169] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkylene). The two bonds in the alkylene group can be attached to two separate atoms, or to the same atom. The alkylene group preferably contains from 1 to 6 carbon atoms (i.e., C 1-6 alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2- or ), 1,1-ethylidene (-CH(CH3)-), 1,2-ethylidene (-CH2CH2)-, 1,1-propylidene (-CH(CH2CH3)-), 1,2-propylidene (-CH2CH(CH3)-), 1,3-propylidene (-CH2CH2CH2-), and 1,4-butylidene (-CH2CH2CH2CH2-), and the like.

[0170] The term "haloalkylene" refers to a divalent alkyl group substituted with a halogen, wherein alkyl is as defined above, for example haloC 1-10 alkylene, preferably haloC 1-6 alkylene. Non-limiting examples of haloalkylene groups include, but are not limited to, monofluoromethylene (e.g., -CHF-, ), difluoromethylene (e.g., -CF2- or ), fluorinated ethylene , and the like. BRIEF DESCRIPTION OF DRAWINGS

[0171] Figure 1 is the effect of compound 006 on serum calcium in a single-dose rat TPTx model;

[0172] Figure 2 is the effect of compound 006 on serum phosphorus in a single-dose rat TPTx model;

[0173] Figure 3 is the effect of Compound 006 on serum calcium at the last dose in a 7-day continuous dosing TPTx model in rats;

[0174] Figure 4 is the effect of Compound 006 on serum phosphorus at the last dose in a 7-day continuous dosing TPTx model in rats;

[0175] Figure 5 is the effect of Compound 006 on serum calcium in a 7-day continuous dosing TPTx model in rats;

[0176] Figure 6 is the effect of Compound 006 on serum phosphorus in a 7-day continuous dosing TPTx model in rats. DETAILED DESCRIPTION

[0177] The technical solutions of the present disclosure will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained the present disclosure, and should not be interpreted as limiting the scope of protection of the present disclosure. Any technology realized based on the above description of the present disclosure is covered within the scope intended to be protected by the present disclosure.

[0178] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0179] NMR: Bruker AVANCE NEO 400MHz nuclear magnetic resonance spectrometer

[0180] HPLC: Agilent 1200 Infinity

[0181] Example 1

[0182] 1-(6-((2S)-3-(9-oxa-3-azabicyclo[3.3.1]non-3-yl)-1,1,1,1-trifluoro-2-hydroxy-3-oxoprop-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea

[0183] Step 1 Synthesis of compound 001b (ethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoate)

[0184] At room temperature, tert-butyl (4-bromophenyl)carbamate (30 g, 110.24 mmol) was dissolved in tetrahydrofuran (800 mL), sodium hydride (4.41 g, 110.24 mmol) was added at 0 °C under nitrogen protection, the reaction solution was stirred at 0 °C for half an hour, then the temperature of the reaction solution was reduced to -70 °C, 2.5 N n-butyllithium (67 mL, 167.56 mmol) was slowly added, the reaction solution was stirred at -70 °C for half an hour, then 3,3,3-trifluoroacetone acid ethyl ester (28.13 g, 165.36 mmol) was added, the reaction solution was continued to be stirred at -70 °C for 1.5 hours. The reaction solution was quenched with ammonium chloride solution, extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-3:1) to give the target compound 001b (18.2 g, yield 45.44%) as a yellow oil.

[0185] Second step Synthesis of compound 001c (2-(4-aminophenyl)-3,3,3-trifluoro-2- hydroxypropanoic acid ethyl ester)

[0186] At room temperature, 001b (2.5 g, 6.88 mmol) and trifluoroacetic acid (12 mL) were dissolved in dichloromethane (12 mL), the reaction solution was stirred at room temperature for 2 hours. After the reaction solution was concentrated, ethyl acetate (50 mL) was added to the reaction solution, the pH value was adjusted to 8 with aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL*2), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound 001c (1.67 g, yield 92.21%) as a yellow solid.

[0187] MS: (ESI, m / z): 263.9 [M+H] +

[0188] Third step Synthesis of compound 001d (2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3- trifluoro-2-hydroxypropanoic acid ethyl ester)

[0189] 001c (1.8 g, 6.84 mmol) was dissolved in glacial acetic acid (12 mL), potassium thiocyanate (2.33 g, 23.94 mmol) was added, the reaction was stirred at room temperature for 1 hour, then bromine (1.20 g, 7.52 mmol) was dissolved in glacial acetic acid (1 mL), slowly added to the above reaction, the reaction was stirred at room temperature overnight. The reaction was filtered, washed with ethyl acetate (50 mL), the filtrate was concentrated, neutralized with NaHCO3 aqueous solution, extracted with ethyl acetate (60 mL x 3), the organic phase was combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-2:1) to obtain the target compound 001d (1.6 g, yield 73.05%) as a yellow solid.

[0190] MS: (ESI, m / z): 320.9 [M+H] +

[0191] Fourth step Synthesis of compound 001e (3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl) ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid ethyl ester)

[0192] 001d (4 g, 12.49 mmol) was dissolved in N,N-dimethylformamide (30 mL), p-fluorophenyl isocyanate (2.57 g, 18.73 mmol) was slowly added, and the reaction was stirred at room temperature for 2 hours. NH4Cl (100 mL) was added to the reaction, extracted with ethyl acetate (60 mL x 3), the organic phase was combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-0:1) and reverse phase (0.01% formic acid / acetonitrile) column to obtain the target compound 001e (3.7 g, yield 64.77%) as a yellow solid.

[0193] MS: (ESI, m / z): 458.0 [M+H] +

[0194] Fifth step Synthesis of compound 001f ((S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl) ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid ethyl ester)

[0195] Compound 001e (7 g, 8.09 mmol) was separated by SFC, the conditions were as follows (System: Waters SFC 150; Column: Chromatography column specification: 250*30mm 10pm; mobile phase: A supercritical CO2, mobile phase B: ethanol (+0.1% 7.0 mol / l amine methanol solution); A:B=50:50; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 4.0 mL; cycle time: 8.5 min; solvent: MeOH: distilled grade, supercritical CO2: food grade), to obtain compound 001f (retention time: 2.378 min, 1.4 g, 24.51%) as a white solid.

[0196] MS: (ESI, m / z): 458.1 [M+H] +

[0197] Sixth step Synthesis of compound 001g ((S)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid)

[0198] 001f (700 mg, 1.53 mmol) and lithium hydroxide (293.15 mg, 12.24 mmol) were dissolved in methanol (25 mL) and water (12 mL) at room temperature, and the reaction solution was stirred at 50 °C for 1 hour. The reaction solution was concentrated, the PH value was adjusted to 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound 001g (630 mg, yield 96.32%) as a white solid.

[0199] MS: (ESI, m / z): 430.0 [M+H] +

[0200] Seventh step Synthesis of compound 001

[0201] To a solution of 001g (40 mg, 0.093 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (35.66 mg, 0.19 mmol) and 1-hydroxybenzotriazole (25.13 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added 9-oxo-3- azabicyclo[3.3.1]nonane hydrochloride (76.09 mg, 0.46 mmol) and N,N- diisopropylethylamine (36.06 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 49% B; detection wavelength: 254 nm / 214 nm) to give the target compound 001 (7.92 mg, yield 15.79%) as a white solid.

[0202] 001:

[0203] MS: (ESI, m / z): 457.3 [M+H] +

[0204] 1 H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.51 (s, 1H), 8.46 - 8.00 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.60 - 7.29 (m, 3H), 7.16 (t, J = 8.9 Hz, 2H), 4.32 - 4.13 (m, 1H), 3.99 - 3.83 (m, 1H), 3.66 - 3.55 (m, 1H), 3.49 - 3.37 (m, 2H), 3.09 - 2.94 (m, 1H), 2.41 - 1.74 (m, 1H), 1.73 - 1.46 (m, 3H), 1.42 - 1.24 (m, 1H), 1.21 - 1.00 (m, 1H).

[0205] Example 2

[0206] 1-(6-((2S)-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1,1,1-trifluoro-2-hydroxy-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea

[0207] First Step: Synthesis of compound 002

[0208] To a solution of 001 g (30 mg, 0.070 mmol) in N,N-dimethylformamide (1 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (16.10 mg, 0.084 mmol), 1-hydroxybenzotriazole (11.35 mg, 0.084 mmol), 2-oxa-5-azabicyclo[2.2.2]octane (9.5 mg, 0.084 mmol) and ethyldiisopropylamine (27.14 mg, 0.21 mmol) at room temperature. Stirring at room temperature for 2 h, the product was purified by preparative liquid phase with the following conditions: (Waters 2767 / Qda) preparative column: Sunfire C18 19*250mm*10μm; mobile phase A: 0.1% FA / H20, B: ACN; flow rate: 20 mL / min; gradient: 47%-50% A; Compound 002 (2 mg, yield 5.46%) was obtained as a white solid.

[0209] 002:

[0210] MS: (ESI, m / z): 525.2 [M+H] +

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.43 (s, 1H), 8.19 - 8.04 (m, 1H), 8.03 - 7.91 (m, 1H), 7.64 - 7.54 (m, 3H), 7.48 - 7.33 (m, 1H), 7.14 (t, J = 8.7 Hz, 2H), 4.04 - 3.98 (m, 1H), 3.70 - 3.67 (m, 1H), 2.88 - 2.72 (m, 2H), 1.94 - 1.83 (m, 1H), 1.78 - 1.61 (m, 2H), 1.50 - 1.38 (m, 1H), 1.25 - 1.22 (m, 1H), 1.15 - 1.05 (m, 1H).

[0212] Example 3

[0213] (S)-1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-oxo-3-(5-oxa-8- azaspiro[3.5]non-8-yl)propanoyl)benzo[d]thiazol-2-yl)urea

[0214] To a solution of 001g (35 mg, 0.082 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (31.44 mg, 0.16 mmol) and 1-hydroxybenzotriazole (22.16 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL) was added 5-oxa-8- azaspiro[3.5]nonane (52.14 mg, 0.41 mmol) and N,N-diisopropylethylamine (31.79 mg, 0.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 51%-58% B; detection wavelength: 254 nm / 214 nm) to give compound 003 (18.88 mg, 43.01% yield) as a white solid.

[0215] MS: (ESI, m / z): 539.1 [M+H] +

[0216] 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.33 (s, 1H), 8.23 - 7.99 (m, 2H), 7.76 - 7.64 (m, 1H), 7.59 - 7.43 (m, 3H), 7.17 (t, J = 8.9 Hz, 2H), 4.03 - 3.85 (m, 1H), 3.63 - 3.48 (m, 1H), 3.30 - 2.89 (m, 4H), 1.97 - 1.65 (m, 4H), 1.39 - 1.18 (m, 1H), 0.73 - 0.49 (m, 1H).

[0217] Example 4

[0218] 1-(6-(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan- 2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea 004

[0219] 1-(6-((2S)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,1,1-trifluoro-2-hydroxy-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea

[0220] 1-(6-((2R)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,1,1-trifluoro-2-hydroxy-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea

[0221] First Step: Synthesis of compound 004

[0222] The synthesis method of compound 004a (3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid) refers to Example 1 (the fifth step SFC separation is omitted). To compound 004a (80 mg, 0.19 mmol) in N,N- dimethylformamide (3 mL), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (142 mg, 0.95 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol) and 1-hydroxybenzotriazole (52 mg, 0.38 mmol) were added, N,N- diisopropylethylamine (74 mg, 0.57 mmol) was added dropwise slowly, and the reaction was stirred at room temperature for 2 hours. Water (30 mL) was added to dilute the reaction, and ethyl acetate (50 mL x 3) was used to extract, the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product 004 (45 mg, yield 41.44%) as a light yellow solid.

[0223] Second Step: Synthesis of compound 004-A / 004-B

[0224] 004 (45 mg, 0.086 mmol) was separated by chiral SFC under the following conditions (column specifications: 250*30mm 10pm; mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / l Ammonia in MeOH); flow rate: 50 mL / min; detection wavelength: UV 214 nm; sample dissolution solvent: methanol; single injection amount: 2.0 mL, to obtain 004-A crude (17 mg, RT = 7.27 min) and 004-B crude (17 mg, RT = 9.46 min). 004-A crude was purified by high performance liquid, conditions as follows (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 38%-52% B; detection wavelength: 254 nm / 220 nm), to obtain the target compound 004-A (5.44 mg, yield 12.09%) as a white solid. 004-B crude was purified by high performance liquid, conditions as follows (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 40%-52% B; detection wavelength: 254 nm / 220 nm), to obtain the target compound 004-B (7.10 mg, yield 15.78%) as a white solid.

[0225] 004-A:

[0226] LCMS: (ESI, m / z): 525.1 [M+H] + , RT (min): 7.27

[0227] 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.24 (s, 1H), 8.12 (d, J = 11.2 Hz, 1H), 8.04 (s, 1H), 7.76 - 7.62 (m, 1H), 7.60 - 7.37 (m, 3H), 7.17 (t, J = 8.9 Hz, 2H), 4.52 (d, J = 6.6 Hz, 0.5H), 4.44 (d, J = 5.5 Hz, 0.5H), 4.35 (d, J = 6.6 Hz, 0.5H), 3.89 (d, J = 6.4 Hz, 1H), 3.73 (d, J = 10.5 Hz, 0.5H), 3.56 (s, 1H), 3.50 - 3.46 (m, 0.5H), 3.41 - 3.37 (m, 1H), 2.85 (d, J = 10.5 Hz, 0.5H), 2.01 (d, J = 10.5 Hz, 0.5H), 1.96 - 1.86 (m, 0.5H), 1.84 - 1.67 (m, 2H), 1.65 - 1.55 (m, 0.5H), 1.46 - 1.37 (m, 0.5H), 0.70 - 0.60 (m, 0.5H).

[0228] 004-B:

[0229] LCMS: (ESI, m / z): 525.1 [M+H] + , RT (min): 9.46

[0230] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.26 (s, 1H), 8.17 - 8.08 (m, 1H), 8.04 (s, 1H), 7.78 - 7.59 (m, 1H), 7.57 - 7.37 (m, 3H), 7.17 (t, J = 8.9 Hz, 2H), 4.52 (d, J = 6.6 Hz, 0.5H), 4.44 (d, J = 4.4 Hz, 0.5H), 4.35 (d, J = 6.0 Hz, 0.5H), 3.89 (d, J = 6.1 Hz, 1H), 3.73 (d, J = 10.6 Hz, 0.5H), 3.56 (s, 1H), 3.50 - 3.46 (m, 0.5H), 3.42 - 3.37 (m, 1H), 2.88 - 2.83 (m, 0.5H), 2.01 (d, J = 10.5 Hz, 0.5H), 1.97 - 1.88 (m, 0.5H), 1.82 - 1.67 (m, 2H), 1.65 - 1.57 (m, 0.5H), 1.47 - 1.37 (m, 0.5H), 0.70 - 0.59 (m, 0.5H).

[0231] Example 5

[0232] 1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(6-methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)-3-oxoprop-2-yl)benzo[d]thiazol-2-yl)ureido)urea

[0233] (S)-1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(6-methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)-3-oxoprop-2-yl)benzo[d]thiazol-2-yl)ureido)urea

[0234] (R)-1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(6-methylsulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)-3-oxoprop-2-yl)benzo[d]thiazol-2-yl)ureido)urea

[0235] First Step Synthesis of compound 005b (tert-butyl 6-(3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoyl)-2,6-diazaspiro[3.3]heptane- 2-carboxylate)

[0236] Compound 004a (300 mg, 0.70 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (268.38 mg, 1.4 mmol) and 1-hydroxybenzotriazole (189.17 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (15 mL) and stirred at room temperature for 10 min. tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (208.17 mg, 1.05 mmol) and N,N-diisopropylethylamine (271.40 mg, 2.10 mmol) were added and the reaction was stirred at room temperature for 16 h. Water (50 mL) was added to the reaction and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-0:1) to give the target compound 005b (250 mg, yield 44.02%) as a yellow oil.

[0237] Second Step Synthesis of compound 005c (compound 1-(4-fluorophenyl)-3-(6-(1,1,1- trifluoro-2-hydroxy-3-oxo-3-(2,6-diazaspiro[3.3]heptan-2-yl)prop-2-yl)benzo[d]thiazol-2- yl)urea)

[0238] 005b (200 mg, 0.33 mmol) and trifluoroacetic acid (2 mL) were dissolved in dichloromethane (6 mL) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, the pH value was adjusted to 8 with an aqueous sodium bicarbonate solution, and ethyl acetate (80 mL x 3) was extracted. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound 005c (144 mg, yield 86.15%) as a white solid.

[0239] MS: (ESI, m / z): 510.1 [M+H] +

[0240] Synthesis of compound 005 (1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(6- methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-3-oxoprop-2-yl)benzothiazol-2-yl)urea)

[0241] 005c (150 mg, 0.29 mmol) and triethylamine (88.04 mg, 0.87 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and methanesulfonyl chloride (43.19 mg, 0.38 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was extracted. The combined organic phase was washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-0:100) and high performance liquid chromatography under the following conditions (column specifications: Waters 2767 / QDA Column: Pursuit XRs 10 C18 21.2*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 46%-56% B; detection wavelength: 254 nm / 214 nm; retention time (min): 7.5-8.6) to obtain the target compound 005 (53.83 mg, yield 31.12%).

[0242] MS: (ESI, m / z): 588.1 [M+H] +

[0243] Synthesis of compound 005-A / 005-B

[0244] Compound 005 (52.83 mg, 0.09 mmol) was separated by SFC under the following conditions (System: Waters SFC 150; column: Chromatography column specification: 250*30 mm 10 pm; mobile phase: A supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L amine methanol solution); A:B = 60:40; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 3.0 mL; cycle time: 5.0 min; solvent: MeOH: distilled grade, supercritical CO2: food grade) to obtain compound 005-A (18.05 mg, 10.43%) and compound 005-B (21.04 mg, 12.16%).

[0245] 005-A

[0246] MS: (ESI, m / z): 588.1 [M+H] + , RT (min): 1.471 min

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.23 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.78 - 7.63 (m, 1H), 7.61 - 7.42 (m, 3H), 7.21 - 7.12 (m, 2H), 4.41 (d, J = 10.7 Hz, 1H), 4.11 (q, J = 10.8 Hz, 2H), 4.05 - 3.97 (m, 2H), δ 3.81 (dd, J = 27.1, 9.1 Hz, 2H), 3.62 (d, J = 10.8 Hz, 1H), 2.91 (s, 3H).

[0248] 005-B

[0249] MS: (ESI, m / z): 588.1 [M+H] + , RT (min): 2.104 min

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.59 - 7.46 (m, 3H), 7.21 - 7.12 (m, 2H), 4.41 (d, J = 10.5 Hz, 1H), 4.11 (q, J = 10.8 Hz, 2H), 4.04 - 3.96 (m, 2H), 3.81 (dd, J = 26.9, 9.1 Hz, 2H), 3.61 (d, J = 10.7 Hz, 1H), 2.91 (s, 3H).

[0251] Example 6

[0252] (S)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0253] First Step: Synthesis of compound 006 (S)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0254] To a solution of 001g (50 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) was added 3-(difluoromethyl)cyclobutane-1 -amine (006a, 28 mg, 0.24 mmol), 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) and 1- hydroxybenzotriazole (32 mg, 0.24 mmol) successively. After stirring at room temperature for 10 min, N,N-diisopropylethylamine (47 mg, 0.36 mmol) was added to the reaction mixture. Stirring was continued at room temperature for 1 h. After completion of the reaction, ethyl acetate (10 mL) was added to the reaction mixture and washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250 mm, 10 um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 62%-79% B; detection wavelength: 254 nm / 220 nm; retention time (min): 7.50-8.20) to give the target compound 006 (9.22 mg, yield 14.89%).

[0255] LCMS: (ESI, m / z): 531.2 [M+H] +

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.47 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.66 - 7.62 (m, 2H), 7.57 - 7.53 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.39 - 4.33 (m, 1H), 2.95 - 2.80 (m, 3H), 2.73 - 2.67 (m, 1H).

[0257] Example 7

[0258] 1-(4-Fluorophenyl)-3-(6-((2S)-1,1,1-trifluoro-2-hydroxy-3-(8-hydroxy-8-methyl-3- azabicyclo[3.2.1]octan-3-yl)-3-oxopropanoic-2-yl)benzo[d]thiazol-2-yl)urea007

[0259] First Step: Synthesis of compound 007

[0260] To compound 001g (30 mg, 0.070 mmol) in N,N-dimethylformamide (2 mL) was added 8-methyl-3-azabicyclo[3.2.1]octan-8-ol trifluoroacetate (007a, 54 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.084 mmol) and 1-hydroxybenzotriazole (12 mg, 0.84 mmol), N,N-diisopropylethylamine (27 mg, 0.21 mmol) was added dropwise slowly, the reaction was stirred at room temperature for 2 hours. To the reaction was added water (30 mL) to dilute, extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was further purified by the following conditions (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 47% B; detection wavelength: 254 nm / 220 nm; retention time (min): 8.80-9.60) to give the target compound 007 (4.04 mg, yield 15.78%).

[0261] LCMS: (ESI, m / z): 553.2 [M+H] +

[0262] 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.48 (s, 1H), 8.08 - 8.02 (m, 1H), 7.99 - 7.88 (m, 1H), 7.72 - 7.62 (m, 1H), 7.59 - 7.27 (m, 3H), 7.16 (t, J = 8.9 Hz, 2H), 4.80 - 4.51 (m, 1H), 4.06 - 3.74 (m, 1H), 3.63 - 3.47 (m, 1H), 3.28 - 3.20 (m, 2H), 3.19 - 3.12 (m, 1H), 2.43 - 2.37 (m, 1H), 1.68 - 1.61 (m, 1H), 1.55 - 1.44 (m, 1H), 1.41 - 1.21 (m, 1H), 1.20 - 1.15 (m, 1H), 1.11 - 0.94 (m, 4H).

[0263] Example 8

[0264] (2S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-(2-(S-methylsulfonamidyl)ethyl)propanamide008

[0265] First Step: Synthesis of Compound 008a ((S)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(2-(methylthio)ethyl)propanamide)

[0266] 001g (100 mg, 0.23 mmol) was added to a solution of N,N-dimethylformamide (1 mL), followed by 2-(thiomethyl)ethylamine hydrochloride (42 mg, 0.46 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmol) and 1- hydroxybenzotriazole (62 mg, 0.46 mmol). After stirring at room temperature for 10 min, N,N-diisopropylethylamine (89 mg, 0.69 mmol) was added to the reaction solution. Stirring was continued at room temperature for 2 h. After the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution and washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by C18 reverse phase to obtain the target product 008a (40 mg, yield 34.18%) as a light yellow solid.

[0267] LCMS: (ESI, m / z): 503.2 [M+H] +

[0268] Step 2: Synthesis of compound 008 (2S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(2-(S-methylsulfonamidyl)ethyl)propanamide

[0269] 008a (40 mg, 0.08 mmol) was added to a solution of absolute ethanol (2 mL), then iodobenzene diacetate (77 mg, 0.24 mmol) and ammonium acetate (25 mg, 0.32 mmol) were added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then ethyl acetate (10 mL) was added and washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 35%-45% B; detection wavelength: 254 nm / 220 nm; retention time (min): 8.10-9.30) to obtain the target compound 008 (11.37 mg, yield 26.77%).

[0270] LCMS: (ESI, m / z): 534.1 [M+H] +

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.44 (s, 1H), 8.56-8.50 (m, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.67-7.63 (m, 2H), 7.57-7.53 (m, 2H), 7.19-7.14 (m, 2H), 3.80 (s, 1H), 3.58-3.52 (m, 2H), 3.22-3.14 (m, 2H), 2.86 (d, J = 2.3 Hz, 3H).

[0272] Example 9

[0273] 1-(4-Fluorophenyl)-3-(6-((2S)-1,1,1-trifluoro-2-hydroxy-3-(2-hydroxy-2-methyl-5-oxa-8- azaspiro[3.5]non-8-yl)-3-oxopropanoic acid-2-yl)benzo[d]thiazol-2-yl)urea

[0274] Step 1: Synthesis of compound 009a (1-(4-fluorophenyl)-3-(6-[(2S)-1,1,1- trifluoro-2-hydroxy-3-oxo-3-(2-oxo-5-oxa-8-yl)propan-2-yl]-1,3-benzothiazol-2- yl)urea)

[0275] To a solution of 001g (96 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was added 5-oxa-8-aza[3.5]nonan-2-one (46.59 mg, 0.33 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50.61 mg, 0.26 mmol) and 1-hydroxybenzotriazole (35.67 mg, 0.26 mmol), the mixture was stirred at room temperature for 5 min. Ethyldiisopropylamine (85.30 mg, 0.66 mmol) was added, the mixture was continued to stir at room temperature for 1 h. Diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 60%) to give the target compound 009a (10 mg, yield: 8.09%) as a light yellow oil.

[0276] LCMS: (ESI, m / z): 553.1 [M+H]+

[0277] Step 2: Synthesis of compound 009 1-(4-fluorophenyl)-3-(6-((2S)-1,1,1-trifluoro-2- hydroxy-3-(2-hydroxy-2-methyl-5-oxa-8-azaspiro[3.5]nonan-8-yl)-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)urea

[0278] To a solution of 009a (10 mg, 0.018 mmol) in N,N-dimethylformamide (2 mL) was added methylmagnesium chloride (13.46 mg, 0.18 mmol) at 0 °C, the mixture was stirred at room temperature for 3 h. Aqueous ammonium chloride solution (5 mL) and 6N aqueous hydrochloric acid solution were added at 0 °C, stirred at room temperature for 3 h, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product 009.

[0279] Step 3: Synthesis of compound 009-A / 009-B

[0280] Compound 009 was purified by high performance liquid chromatography with the following conditions (column specification: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10 pm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 43% B; detection wavelength: 254 nm / 220 nm), to obtain target compounds 009-A (1.09 mg, yield: 10.49%), 009-B (1.07 mg, yield: 10.29%).

[0281] 009-A:

[0282] LCMS: (ESI, m / z): 569.3 [M+H] + , RT (min): 9.3-10.1

[0283] 1 H NMR (400 MHz, DMSO-d6) d 10.92 (s, 1H), 9.19 (s, 1H), 8.22 - 8.04 (m, 2H), 7.79 - 7.67 (m, 1H), 7.57 - 7.50 (m, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 8.5 Hz, 2H), 5.75 (s, 1H), 5.10 - 4.66 (m, 1H), 4.05 - 3.86 (m, 1H), 3.20 - 2.91 (m, 4H), 2.00 - 1.77 (m, 3H), 1.64 - 1.47 (m, 1H), 1.39 - 1.02 (m, 3H).

[0284] 009-B:

[0285] LCMS: (ESI, m / z): 569.3 [M+H] + , RT (min): 10.6-11.6

[0286] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.20 (s, 1H), 8.28 - 8.14 (m, 1H), 8.08 - 7.94 (m, 1H), 7.80 - 7.66 (m, 1H), 7.58 - 7.50 (m, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.18 (t, J = 8.5 Hz, 2H), 5.77 - 5.47 (m, 1H), 5.04 - 4.31 (m, 1H), 4.16 - 3.99 (m, 1H), 3.19 - 2.98 (m, 4H), 2.05 - 1.96 (m, 2H), 1.89 - 1.82 (m, 1H), 1.80 - 1.73 (m, 1H), 1.24 - 1.10 (m, 3H).

[0287] Example 10

[0288] (S)-N-((1s,3R)-3-(dimethylamino)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 010-A

[0289] First Step Synthesis of Compound 010a (2,5-dioxopyrrolidin-1-yl (S)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanoate)

[0290] 001g (150 mg, 0.35 mmol) was added to a solution of N,N-dimethylformamide (3 mL), followed by the addition of 1-hydroxypyrrolidine-2,5-dione (64 mg, 0.56 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.56 mmol) and 4-dimethylaminopyridine (5 mg, 0.035 mmol) and stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution and washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude target product 010a (180 mg, yield 100%) as a light yellow solid, which was directly used in the next step.

[0291] LCMS: (ESI, m / z): 527.2 [M+H] +

[0292] Second Step Synthesis of Compound 010b (tert-butyl ((1R,3s)-3-((S)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanamido)cyclobutyl)carbamate)

[0293] To a solution of 010a (180 mg, 0.34 mmol) in tetrahydrofuran (3 mL) was added tert-butyl (cis-3-aminocyclobutyl)carbamate (190 mg, 0.68 mmol), and triethylamine (170 mg, 1.70 mmol) and stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution and washed with saturated brine (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by C18 reverse phase (0.1% FA) to give the target product 010b (170 mg, yield 74.88%) as a light yellow solid.

[0294] LCMS: (ESI, m / z): 598.5 [M+H] +

[0295] Third Step Synthesis of compound 010c ((S)-N-((1s,3R)-3-aminocyclobutyl)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide)

[0296] To a solution of 010b (170 mg, 0.28 mmol) in hydrogen chloride 1,4 dioxane solution (4 M, 2 mL, 8 mmol) was added and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to give white solid 010c (140 mg, crude yield 100%) which was used directly in the next step.

[0297] LCMS: (ESI, m / z): 498.4 [M+H] +

[0298] Fourth Step Synthesis of compound 010-A (S)-N-((1s,3R)-3-(dimethylamino)cyclobutyl)- 3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0299] To a solution of 010c (140 mg, 0.28 mmol) in methanol (3 mL) was added formaldehyde (68 mg, 0.84 mmol, 38% Wt), acetic acid (1.7 mg, 0.028 mmol) and sodium triacetoxyborohydride (180 mg, 0.84 mmol) and stirred at room temperature for 1 h. After completion of the reaction, the reaction was concentrated, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to get the crude product which was purified by high performance liquid chromatography under the following conditions (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 25%-35% B; detection wavelength: 254 nm / 220 nm; retention time (min): 7.20-7.60) to get the target compound 010-A (56.32 mg, yield 38.08%).

[0300] LCMS: (ESI, m / z): 526.1 [M+H] +

[0301] 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (brs, 1H), 8.44-8.30 (m, 1H), 8.30-8.20 (m, 1H), 8.15 (s, 1H), 7.68-7.61 (m, 2H), 7.59-7.53 (m, 2H), 7.21-7.13 (m, 2H), 3.93-3.87 (m, 1H), 2.64-2.52 (m, 1H), 2.46-2.20 (m, 3H), 2.20-2.06 (m, 6H), 2.02-1.89 (m, 1H), 1.88-1.74 (m, 1H).

[0302] Example 11

[0303] (S)-N-((1r,3S)-3-(dimethylamino)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0304] The synthetic method is the same as the synthesis of 010-A in Example 10, replacing tert-butyl (cis-3-aminocyclobutyl)carbamate with tert-butyl (trans-3-aminocyclobutyl)carbamate in the second step to obtain the target compound (S)-N-((1r,3S)-3-(dimethylamino)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide) 010-B.

[0305] LCMS: (ESI, m / z): 526.2 [M+H] + , RT (min): 7.60-8.40

[0306] 1 H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 7.77-7.74 (m, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.54-7.49 (m, 2H), 7.11-7.06 (m, 2H), 4.39-4.32 (m, 1H), 3.88-3.81 (m, 1H), 2.80 (s, 6H), 2.68-2.52 (m, 3H), 2.48-2.41 (m, 1H).

[0307] Example 12

[0308] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-((1s,3R)-3-(methylamino)cyclobutyl)propanamide

[0309] Synthesis of compound 011a (tert-butyl methyl ((1R,3s)-3-((S)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamido)cyclobutyl)carbamate)

[0310] Add 010a (100 mg, 0.19 mmol) into tetrahydrofuran (3 mL), then add tert-butyl (cis-3- aminocyclobutyl)(methyl)carbamate (76 mg, 0.38 mmol) and triethylamine (58 mg, 0.57 mmol), stir at room temperature for 2 hours. After the reaction is completed, add ethyl acetate (30 mL) to dilute the reaction solution, combine the organic phases and wash with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, which is purified by normal phase (petroleum ether: ethyl acetate = 1:1) to obtain the target product 011a (85 mg, yield 73.16%) as a white solid.

[0311] LCMS: (ESI, m / z): 612.2 [M+H] +

[0312] Second Step: Synthesis of compound 011-A

[0313] 011a (40 mg, 0.065 mmol) was added to 4M HC1 / Dioxane (1 mL) at room temperature, the reaction was stirred at room temperature for 1 hour. The reaction was concentrated to get the crude product, the crude product was purified by high performance liquid, the conditions were as follows (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; elution gradient: 65%-75% B; detection wavelength: 254 nm / 220 nm, to get the target compound (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-((1s,3R)-3-(methylamino)cyclobutyl)propanamide 011-A (15.1 mg, yield 45.14%).

[0314] LCMS: (ESI, m / z): 512.4 [M+H] + , RT (min): 8.00-8.50

[0315] 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.36 (s, 2H), 8.13 (s, 1H), 8.08 - 7.65 (m, 1H), 7.64 - 7.54 (m, 4H), 7.15 (t, J = 8.8 Hz, 2H), 4.03 - 3.91 (m, 1H), 3.10 - 2.96 (m, 2H), 2.45 - 2.40 (m, 1H), 2.37 - 2.21 (m, 4H), 2.04 - 1.92 (m, 1H), 1.90 - 1.79 (m, 1H).

[0316] Example 13

[0317] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-((1r,3S)-3-(methylamino)cyclobutyl)propanamide

[0318] The synthetic method is the same as the synthesis of 011-A in Example 12, replacing tert-butyl (cis-3-aminocyclobutyl)(methyl)carbamate with tert-butyl (trans-3-aminocyclobutyl)(methyl)carbamate in the first step to obtain the target compound (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-((1r,3S)-3-(methylamino)cyclobutyl)propanamide 011-B.

[0319] LCMS: (ESI, m / z): 512.1 [M+H] +

[0320] 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.45 (brs, 1H), 8.65 (d, J = 7.6 Hz, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.69 - 7.62 (m, 2H), 7.58 - 7.53 (m, 2H), 7.21 - 7.14 (m, 2H), 4.50 - 4.40 (m, 1H), 3.59 - 3.55 (m, 1H), 2.45 (s, 3H), 2.43 - 2.36 (m, 2H), 2.34 - 2.26 (m, 2H).

[0321] Example 14

[0322] (S)-1-(6-(3-(3-(difluoromethylen)azetidin-1-yl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea

[0323] First Step Synthesis of Compound 012

[0324] To a solution of 001g (20 mg, 0.05 mmol) in N,N-dimethylformamide (2 mL) was added 3-(difluoromethylimino)azepane (012a, 7.41 mg, 0.07 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (10.81 mg, 0.06 mmol) and 1- hydroxybenzotriazole (7.62 mg, 0.06 mmol), the mixture was stirred at room temperature for 5 min. Ethyldiisopropylamine (18.22 mg, 0.14 mmol) was added, the mixture was continued to stir at room temperature for 1 h. Diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, the obtained residue was purified by high performance liquid, conditions as follows (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 53% B; detection wavelength: 254 nm / 220 nm), to give the target compound (S)-1-(6-(3-(3-(difluoromethylene)azetidin-1-yl)-1,1,1-trifluoro-2-hydroxy-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea 012 (16.74 mg, yield: 68.2%).

[0325] LCMS: (ESI, m / z): 517.2 [M+H] + , RT(min): 9.8-11

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.74 - 7.63 (m, 1H), 7.57 - 7.52 (m, 3H), 7.17 (t, J = 8.8 Hz, 2H), 4.93 - 4.88 (m, 1H), 4.58 (brs, 2H), 4.17 - 4.11 (m, 1H).

[0327] Example 15

[0328] (S)-3,3,3-trifluoro-N-(3-(fluoromethylene)cyclobutyl)-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 013

[0329] (S)-3,3,3-trifluoro-N-((S,Z)-3-(fluoromethylene)cyclobutyl)-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0330] (S)-3,3,3-trifluoro-N-((R,E)-3-(fluoromethenyl)cyclobutyl)-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0331] First Step Synthesis of Compound 013 ((2S)-3,3,3-trifluoro-N-(3-(fluoromethenyl)cyclobutyl)-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanamide)

[0332] To 001g (200 mg, 0.47 mmol), 013a (71.29 mg, 0.70 mmol), EDCI (135.15 mg, 0.70 mmol) and HOBt (95.26 mg, 0.70 mmol) were added to DMF (2 mL), then DIEA (182.23 mg, 1.41 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (30 mL) and ethyl acetate (20 mL X 3) were added to the reaction solution, the organic phase was washed with saturated brine (30 mL X 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, and the crude product was purified by reversed-phase preparative chromatography (chromatography column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 55% B; detection wavelength: 254 nm / 220 nm) to obtain compound 013 (140 mg, yield 58.65%).

[0333] Second Step Synthesis of Compound 013-A and 013-B

[0334] The target compound 013 was purified by SFC resolution, and the purification conditions were as follows (K-Prep LAB100G; chromatography column specifications: 250*25mm 10um; mobile phase: A n-hexane, mobile phase B: ethanol (+0.1% 7.0mol / L amine ethanol solution); A:B=85:15; wavelength: 254nm; flow rate: 50mL / min; column temperature: RT; injection volume: 2mL; cycle time: 14min; solvent: EtOH:distilled grade, n-hexane:distilled grade). The target compound 013 was purified by SFC resolution, and the purification conditions were as follows (K-Prep LAB100G; chromatography column specifications: 250*25mm 10um; mobile phase: A n-hexane, mobile phase B: ethanol (+0.1% 7.0mol / L amine ethanol solution); A:B=85:15; wavelength: 254nm; flow rate: 50mL / min; column temperature: RT; injection volume: 2mL; cycle time: 14min; solvent: EtOH:distilled grade, n-hexane:distilled grade).

[0335] 013-A:

[0336] MS: (ESI, m / z): 513.2 [M+H]+ , RT (min): 25-30.5

[0337] 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.56 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.62 (s, 2H), 7.58 - 7.53 (m, 2H), 7.16 (t, J = 8.9 Hz, 2H), 6.65 (d, J = 85.4 Hz, 1H), 4.36 - 4.25 (m, 1H), 3.02 - 2.94 (m, 1H), 2.84 - 2.75 (m, 2H), 2.67 - 2.60 (m, 1H).

[0338] 013-B:

[0339] MS: (ESI, m / z): 513.2 [M+H] + , RT (min): 33-39.5

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 13.24 - 11.07 (m, 1H), 10.13 (s, 1H), 8.63 (d, J = 7.5 Hz, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.58 (s, 3H), 7.12 (t, J = 8.8 Hz, 2H), 6.65 (d, J = 85.6 Hz, 1H), 4.28 (dd, J = 15.4, 7.8 Hz, 1H), 2.88 (d, J = 8.3 Hz, 2H), 2.77 (s, 2H).

[0341] Example 16

[0342] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-(3-methylenecyclobutyl)propanamide

[0343] First Step: Synthesis of compound 014 (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(3-methylenecyclobutyl)propanamide

[0344] Compound 001g (100 mg, 0.23 mmol), 014a (55.01 mg, 0.46 mmol), EDCI (66.14 mg, 0.35 mmol) and HOBt (46.62 mg, 0.35 mmol) were added to DMF (2 mL) at room temperature, and then DIEA (89.18 mg, 0.69 mmol) was added to the reaction solution, which was reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by reverse-phase preparative chromatography (column size: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 56% B; detection wavelength: 254 nm / 220 nm) to obtain compound 014 (31.74 mg, yield 27.56%).

[0345] MS: (ESI, m / z): 495.2 [M+H] + , RT (min): 8.8-10.0

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.24 (s, 1H), 8.54 (d, J = 7.4 Hz, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.65 (s, 2H), 7.61 - 7.49 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.84 - 4.68 (m, 2H), 4.30 - 4.13 (m, 1H), 2.91 - 2.75 (m, 3H), 2.75 - 2.67 (m, 1H).

[0347] Example 17

[0348] (2S)-N-(3-(Difluoromethyl)cyclopentyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 015

[0349] First Step: Synthesis of compound 015 (2S)-N-(3-(Difluoromethyl)cyclopentyl)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0350] To a solution of compound 001g (100 mg, 0.23 mmol) and 3-(difluoromethyl)cyclopentane-1-amine hydrochloride (61.24 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (88.18 mg, 0.46 mmol), 1- hydroxybenzotriazole (62.16 mg, 0.46 mmol) and ethyldiisopropylamine (148.63 mg, 1.15 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was purified by Prep-HPLC (column size: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient elution: 60%-65% B, detection wavelength: 254 nm / 220 nm) to give the target product 015 (13 mg, 10.25% yield).

[0351] MS: (ESI, m / z): 545.1 [M+H] + , RT (min): 7.8-9.0

[0352] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.25 (s, 1H), 8.26 - 8.10 (m, 2H), 7.81 (s, 1H), 7.74 - 7.59 (m, 2H), 7.58 - 7.49 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 4.21 - 4.08 (m, 1H), 2.42 - 2.08 (m, 4H), 1.96 - 1.79 (m, 1H), 1.78 - 1.52 (m, 1H).

[0353] Example 18

[0354] (S)-1-(6-(3-(3-(difluoromethyl)pyrrolidin-1-yl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea 016

[0355] First Step: Synthesis of compound 016 (S)-1-(6-(3-(3-(difluoromethyl)pyrrolidin-1-yl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea

[0356] To a solution of compound 001g (200 mg, 0.47 mmol), 3-(difluoromethyl)pyrrolidine hydrochloride (55.98 mg, 0.47 mmol), EDCI (135.15 mg, 0.70 mmol) and HOBt (95.26 mg, 0.70 mmol) in DMF (2 mL) was added DIPEA (182.23 mg, 1.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to get the crude product which was purified by reverse phase preparative chromatography (column size: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient elution: 55% B; detection wavelength: 254 nm / 220 nm) to get the desired product 016 (35.03 mg, yield 14.18%).

[0357] MS: (ESI, m / z): 531.2 [M+H] + , RT (min): 8.0-9.6

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.25 (s, 1H), 8.11 - 8.03 (m, 2H), 7.75 - 7.62 (m, 1H), 7.57 - 7.51 (m, 2H), 7.48 - 7.43 (m, 1H), 7.18 (t, J = 8.8 Hz, 2H), 4.40 - 4.21 (m, 0.5H), 4.19 - 4.01 (m, 1H), 3.73 - 3.65 (m, 1H), 3.62 - 3.45 (m, 0.5H), 3.27 - 3.18 (m, 0.5H), 2.80 - 2.74 (m, 0.5H), 2.47 - 2.37 (m, 1.5H), 2.23 - 2.17 (m, 0.5H).

[0359] Example 19

[0360] (S)-N-(3,3-difluoropropenyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 017

[0361] First Step: Synthesis of compound 017 (S)-N-(3,3-difluoropropenyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0362] To a solution of 001 g (50 mg, 0.12 mmol), 3,3-difluoroprop-2-en-1-amine hydrochloride (22.34 mg, 0.24 mmol), EDCI (34.51 mg, 0.18 mmol) and HOBt (24.32 mg, 0.18 mmol) in DMF (2 mL) was added DIPEA (46.53 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by reverse phase preparative chromatography (column size: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 54%-55% B; detection wavelength: 254 nm / 220 nm; retention time (min): 8.3-9.2) to give the target product 017 (9.36 mg, yield 15.93%).

[0363] MS: (ESI, m / z): 505.2 [M+H] + , RT (min): 8.3-9.2

[0364] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.21 (s, 1H), 8.51 (t, J = 5.7 Hz, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.74 - 7.61 (m, 2H), 7.58 - 7.49 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.72 - 4.34 (m, 1H), 3.77 - 3.65 (m, 2H).

[0365] Example 20

[0366] N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(4-fluoro-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 018

[0367] (S)-N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(4-fluoro-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0368] (R)-N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(4-fluoro-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0369] Step 1: Synthesis of compound 018b (N-(4-bromo-2-fluorophenyl) carbamate)

[0370] To a solution of 4-bromo-2-fluoroaniline (5 g, 26.31 mmol, 018a) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)amide (8.7 g, 52 mmol) at 0 °C. The reaction was stirred at 0 °C for half an hour, then a solution of tert-butyloxycarbonyl anhydride (5.74 g, 26.31 mmol) in tetrahydrofuran (6 mL) was added. The reaction was stirred at room temperature for 15 minutes. It was quenched with aqueous ammonium chloride solution, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-20%) to give the target compound 018b (7 g, yield: 82.52%) as yellow oil.

[0371] Step 2: Synthesis of compound 018c (ethyl 2-(4-(((tert-butoxy)carbonyl)amino)-3- fluorophenyl)-3,3-trifluoro-2-hydroxypropanoate)

[0372] To a solution of 018b (3 g, 10.34 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (2.32 g, 36.19 mmol) at -78 °C. The reaction was stirred at -78 °C for half an hour, then ethyl 3,3,3-trifluoro-2-oxopropanoate (7.03 g, 41.36 mmol) was added. The reaction was stirred at -78 °C for 1 hour. It was quenched with aqueous ammonium chloride solution, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-30%) to give the target compound 018c (850 mg, yield: 19.40%) as yellow oil.

[0373] Step 3: Synthesis of compound 018d (ethyl 2-(4-amino-3-fluorophenyl)-3,3,3- trifluoro-2-hydroxypropanoate)

[0374] To a solution of 018c (830 mg, 2.18 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (6.1 g, 53.67 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated to give the crude 018d (630 mg, yield: 82.34%) as yellow oil, which was used directly in the next step.

[0375] Step 4: Synthesis of compound 018e (ethyl 2-(2-amino-4-fluorobenzo[d]thiazol-6-yl)- 3,3,3-trifluoro-2-hydroxypropanoate)

[0376] To a solution of 018d (610 mg, 2.17 mmol) in acetic acid (7 mL) was added potassium thiocyanate (1.69 g, 17.36 mmol) and the reaction was stirred at room temperature for 2 h. Liquid bromine (520.18 mg, 3.25 mmol) was added at 0 °C and the reaction was stirred at room temperature overnight. The reaction was adjusted to pH = 13 with aqueous potassium carbonate solution, diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give the target compound 018e (330 mg, yield: 40.47%) as a yellow oil.

[0377] LCMS: (ESI, m / z): 339.0 [M+H] +

[0378] Fifth step Synthesis of compound 018f (ethyl 3,3,3-trifluoro-2-(4-fluoro-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoate)

[0379] To a solution of 018e (310 mg, 0.92 mmol) in dichloromethane (5 mL) was added 1-fluoro-4-isocyanatobenzene (378.42 mg, 2.76 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated to give a yellow oil. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-70%) to give the target compound 018f (240 mg, yield: 52.34%) as a yellow oil.

[0380] LCMS: (ESI, m / z): 476.2 [M+H] +

[0381] Sixth step Synthesis of compound 018g (3,3,3-trifluoro-2-(4-fluoro-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid)

[0382] To a solution of 018f (240 mg, 0.50 mmol) in methanol (1 mL) was added a solution of lithium hydroxide (119.75 mg, 5 mmol) in water (1 mL) and the reaction was stirred at 50 °C for 1 h. The pH was adjusted to 3 and the reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow solid. The crude product was used directly in the next step.

[0383] LCMS: (ESI, m / z): 448.1 [M+H] +

[0384] Step 7. Synthesis of compound 018-A / 018-B

[0385] To a solution of 018g (130 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added 3-(difluoromethyl)imidazolidine (44.9 mg, 0.38 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (83.39 mg, 0.43 mmol) and 1- hydroxybenzotriazole (58.78 mg, 0.43 mmol), the reaction was stirred at room temperature for 10 min, ethyldiisopropylamine (112.44 mg, 0.87 mmol) was added, the reaction was continued to stir at room temperature for 1 h. The reaction was rotary evaporated to get the crude product, the obtained residue was purified by high performance liquid, the conditions were as follows (column specification: Waters 2767 / QDA Column: Pursuit XRs C18 21.2*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 67% B~70% B; detection wavelength: 254 nm / 220 nm, to get compound 018, which was directly resolved, the resolving conditions were as follows (column specification: Chiralpak IC 250*50mm 10μm; mobile phase A: supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol solution); A:B=50:50, flow rate: 140 mL / min; detection wavelength: UV 214 nm; column temperature: RT; back pressure: 100 bar; injection volume: 8 mL cycle time: 14 min, to get target compound 018-A (10.65 mg, yield: 6.55%); to get 018-B target compound (11.84 mg, yield: 7.28%). 250*50mm 10μm; mobile phase A: supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol solution); A:B=50:50, flow rate: 140 mL / min; detection wavelength: UV 214 nm; column temperature: RT; back pressure: 100 bar; injection volume: 8 mL cycle time: 14 min, to get target compound 018-A (10.65 mg, yield: 6.55%); to get 018-B target compound (11.84 mg, yield: 7.28%).

[0386] 018-A:

[0387] MS: (ESI, m / z): 549.2 [M+H] + , RT(min): 6-9.5

[0388] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.74 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.66 - 7.49 (m, 2H), 7.37 - 7.31 (m, 1H), 7.11 (t, J = 8.8 Hz, 2H), 4.46 - 4.24 (m, 1H), 3.03 - 2.85 (m, 3H), 2.76 - 2.70 (m, 1H).

[0389] 018-B:

[0390] MS: (ESI, m / z): 549.2 [M+H] + , RT (min): 12.4-17

[0391] 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.74 (d, J = 7.3 Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.62 - 7.52 (m, 2H), 7.37 - 7.33 (m, 1H), 7.11 (t, J = 8.8 Hz, 2H), 4.48 - 4.20 (m, 1H), 2.99 - 2.87 (m, 2H), 2.82 - 2.75 (m, 1H), 2.74 - 2.68 (m, 1H).

[0392] Example 21

[0393] N-(3-(Difluoromethyl)cyclobutyl)-2-(2-(3-(2,4-difluorophenyl)ureido)benzo[d]thiazol-6- yl)-3,3,3-trifluoro-2-hydroxypropanamide 019

[0394] (S)-N-(3-(Difluoromethyl)cyclobutyl)-2-(2-(3-(2,4-difluorophenyl)ureido)benzo[d]thiazol-6- yl)-3,3,3-trifluoro-2-hydroxypropanamide

[0395] (R)-N-(3-(Difluoromethyl)cyclobutyl)-2-(2-(3-(2,4-difluorophenyl)ureido)benzo[d]thiazol-6- yl)-3,3,3-trifluoro-2-hydroxypropanamide

[0396] Synthesis of compound 019b (ethyl 2-(2-(3-(2,4-difluorophenyl)ureido)benzo[d]thiazol-6- yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[0397] To a solution of ethyl 2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2- hydroxypropanoate (200 mg, 0.62 mmol) in dichloromethane (5 mL), 2,4- difluorophenyl isocyanate (106 mg, 0.68 mmol, 019a) was added dropwise slowly and the reaction was stirred at room temperature for 2 h. To the reaction, water (30 mL) was added to dilute and extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target product 019b (230 mg, yield 77.48%) as a light yellow solid.

[0398] LCMS: (ESI, m / z): 476.1 [M+H] +

[0399] Second Step Synthesis of compound 019c (Ethyl 2-(2-(3-(2,4-difluorophenyl) ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[0400] To a solution of compound 019b (200 mg, 0.42 mmol) in methanol (8 mL), lithium hydroxide (100 mg, 4.2 mmol) and water (2 mL) were added slowly and the reaction was stirred at 50 °C for 1 h. The reaction was concentrated in vacuo, the concentrate was diluted with water (30 mL) and 1 N aqueous hydrochloric acid was added slowly to adjust pH = 3-4, extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the target product 019c (160 mg, yield 85.02%) as a light yellow solid crude. It was used directly in the next step.

[0401] LCMS: (ESI, m / z): 448.1 [M+H] +

[0402] Third Step Synthesis of compound 019 (N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(2,4- difluorophenyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide)

[0403] To 019c (100 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol) and 1- hydroxybenzotriazole (45 mg, 0.33 mmol) and the reaction was stirred at room temperature under nitrogen for 10 min. To the reaction was added 3-(difluoromethyl)cyclobutane-l- amine hydrochloride (41 mg, 0.26 mmol) and N,N-diisopropylethylamine (86 mg, 0.66 mmol) and the reaction was stirred at room temperature under nitrogen for 2 h. To the reaction was added water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by high performance liquid chromatography under the following conditions (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 60% B; detection wavelength: 254 nm / 220 nm) to give the target compound 019 (37 mg, yield 30.18%).

[0404] LCMS: (ESI, m / z): 549.2 [M+H] +

[0405] 1 H NMR (400 MHz, DMSO-d6) d 11.25 (s, 1H), 9.16 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H), 8.09 - 8.00 (m, 1H), 7.89 (s, 1H), 7.71 - 7.61 (m, 2H), 7.42 - 7.33 (m, 1H), 7.14 - 7.07 (m, 1H), 4.43 - 4.28 (m, 1H), 2.98 - 2.78 (m, 3H), 2.73 - 2.65 (m, 1H).

[0406] Fourth Step Synthesis of compound 019-A / 019-B

[0407] Compound 019 (35 mg, 0.28 mmol) was separated by chiral SFC under the following conditions (column specification: Chiralpak IC, 20*250mm, 5um; mobile phase A: 0.1% FA in CO2, mobile phase B: 0.1% FA in MeOH; flow rate: 15 mL / min; elution gradient: 60% B; detection wavelength: 220 nm / 254 nm) to give compound 019-A (15 mg, yield 42.86%) and compound 019-B (15 mg, yield 42.86%). 250*30mm 10pm; mobile phase A: supercritical CO2, mobile phase B: isopropanol (+0.1% 7.0 mol / L ammonia methanol solution); flow rate: 140 mL / min; detection wavelength: UV 214 nm; A:B = 70:30; flow rate: 140 mL / min; column temperature: RT; injection volume: 3 mL; cycle time: 3.2 min; solvent: methanol (25 mL), to obtain crude product 019-A (11.20 mg, purity: 32%) and crude product 019-B (14.56 mg, purity: 41.6%).

[0408] Crude product 019-A was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10pm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 60% B; detection wavelength: 254 nm / 220 nm, to obtain target compound 019-A (6.69 mg, yield 19.11%).

[0409] Crude product 019-B was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10pm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 60% B; detection wavelength: 254 nm / 220 nm, to obtain target compound 019-B (8.44 mg, yield 24.11%).

[0410] 019-A:

[0411] LCMS: (ESI, m / z): 549.3 [M+H] + , RT (min): 2.4-3.3

[0412] 1 H NMR (400 MHz, DMSO-d6) d 11.53 (s, 1H), 9.32 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 8.07 - 7.98 (m, 1H), 7.92 (s, 1H), 7.73 - 7.54 (m, 2H), 7.43 - 7.28 (m, 1H), 7.16 - 7.05 (m, 1H), 4.42 - 4.30 (m, 1H), 2.99 - 2.78 (m, 3H), 2.73 - 2.66 (m, 1H).

[0413] 019-B:

[0414] 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.41 (s, 1H), 8.74 (d, J = 7.7 Hz, 1H), 8.15 (s, 1H), 8.06 - 7.98 (m, 1H), 7.93 (s, 1H), 7.69 - 7.56 (m, 2H), 7.40 - 7.29 (m, 1H), 7.16 - 7.01 (m, 1H), 4.43 - 4.28 (m, 1H), 2.97 - 2.79 (m, 3H), 2.73 - 2.66 (m, 1H).

[0415] Example 22

[0416] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluoro-2- methoxyphenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 020

[0417] The target compound 020 was prepared according to the same method as in Example 21, using compound 019a replaced by compound 020a.

[0418] MS: (ESI, m / z): 561.3 [M+H] +

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.92 (s, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 1.1 Hz, 1H), 8.07 (dd, J = 9.0, 6.3 Hz, 1H), 7.89 (s, 1H), 7.71 - 7.63 (m, 2H), 7.03 (dd, J = 10.7, 2.8 Hz, 1H), 6.81 - 6.75 (m, 1H), 4.39 - 4.33 (m, 1H), 3.92 (s, 3H), 2.98 - 2.82 (m, 3H), 2.72 - 2.67 (m, 1H).

[0420] Example 23

[0421] 2-(2-(3-(2-chloro-4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxypropanamide 021

[0422] The target compound 021 was prepared according to the same method as in Example 21, using compound 019a replaced by compound 021a.

[0423] MS: (ESI, m / z): 565.2 [M+H] +

[0424] 11 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.03 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.19 (s, 1H), 8.16 - 8.08 (m, 1H), 7.89 (s, 1H), 7.68 (dd, J = 21.8, 8.9 Hz, 2H), 7.55 (dd, J = 8.5, 2.9 Hz, 1H), 7.32 - 7.20 (m, 1H), 4.52 - 4.22 (m, 1H), 3.00 - 2.86 (m, 2H), 2.86 - 2.71 (m, 2H).

[0425] Example 24

[0426] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(4- methoxyphenyl)ureido)benzo[d]thiazol-6-yl)propanamide 022

[0427] The target compound 022 was prepared by the same method as Example 21, by replacing the raw material compound 019a with compound 022a.

[0428] MS: (ESI, m / z): 543.2 [M+H] +

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.29 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.69 - 7.55 (m, 2H), 7.47 - 7.39 (m, 2H), 6.96 - 6.88 (m, 2H), 4.41 - 4.30 (m, 1H), 3.74 (s, 3H), 2.98 - 2.80 (m, 3H), 2.75 - 2.68 (m, 1H).

[0430] Example 25

[0431] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(2,3,4- trifluorophenyl)ureido)benzo[d]thiazol-6-yl)propanamide 023

[0432] The synthetic method is the same as Example 21, and the raw material compound 019a is replaced by compound 023a to give the target compound 023.

[0433] MS: (ESI, m / z): 567.2 [M+H] +

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.25 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.88 - 7.78 (m, 1H), 7.74 - 7.64 (m, 2H), 7.38 - 7.30 (m, 1H), 4.40 - 4.30 (m, 1H), 2.98 - 2.80 (m, 3H), 2.75 - 2.68 (m, 1H).

[0435] Example 26

[0436] 2-(2-(3-(2-cyano-4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxypropanamide 024

[0437] The synthetic method is the same as Example 21, and the raw material compound 019a is replaced by compound 024a to give the target compound 024.

[0438] MS: (ESI, m / z): 556.3 [M+H] +

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 11.64 (s, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.96 - 7.83 (m, 2H), 7.80 - 7.68 (m, 1H), 7.65 - 7.58 (m, 1H), 7.29 - 7.20 (m, 1H), 4.42 - 4.31 (m, 1H), 2.99 - 2.72 (m, 4H).

[0440] Example 27

[0441] N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(3,4-difluorophenyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide 025

[0442] The synthetic method is the same as Example 21, and the raw material compound 019a is replaced by compound 025a to produce the target compound 025.

[0443] MS: (ESI, m / z): 548.8 [M+H] +

[0444] 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.47 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.79 - 7.69 (m, 1H), 7.64 (s, 2H), 7.45 - 7.33 (m, 1H), 7.32 - 7.20 (m, 1H), 4.42 - 4.30 (m, 1H), 2.97 - 2.79 (m, 3H), 2.73 - 2.66 (m, 1H).

[0445] Example 28

[0446] N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[4,5-b]pyridin-6-yl)-2-hydroxypropanamide 026

[0447] The synthetic method is the same as Example 20, and the raw material compound 018a is replaced by compound 026a to produce the target compound 026.

[0448] MS: (ESI, m / z): 532.1 [M+H] +

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.22 (s, 1H), 8.86 (d, J = 7.7 Hz, 1H), 8.72 - 8.53 (m, 2H), 8.13 (s, 1H), 7.56 - 7.51 (m, 2H), 7.21 - 7.16 (m, 2H), 4.44 - 4.33 (m, 1H), 2.99 - 2.80 (m, 3H), 2.77 - 2.69 (m, 1H).

[0450] Example 29

[0451] 2-(4-(Difluoromethoxy)-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxypropanamide 027

[0452] The synthetic method is the same as Example 20, and the starting material compound 018a is replaced by compound 027a to produce the target compound 027.

[0453] MS: (ESI, m / z): 597.1 [M+H] +

[0454] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.13 (s, 1H), 8.77 (d, J = 7.5 Hz, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 7.56 - 7.51 (m, 2H), 7.46 (s, 1H), 7.41 - 7.11 (m, 3H), 4.41 - 4.31 (m, 1H), 2.97 - 2.80 (m, 3H), 2.73 - 2.66 (m, 1H).

[0455] Example 30

[0456] (2S)-N-(3-(chloromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 028

[0457] The synthetic method is the same as Example 15, and the starting material compound 018a is replaced by compound 028a to produce the target compound 028.

[0458] MS: (ESI, m / z): 529.1 [M+H] +

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.25 (s, 1H), 8.67 (d, J = 7.5 Hz, 1H), 8.16 (s, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.59 - 7.48 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 6.14 - 5.94 (m, 1H), 4.38 - 4.20 (m, 1H), 2.97 - 2.80 (m, 3H), 2.73 - 2.67 (m, 1H).

[0460] Example 31

[0461] (2S)-3,3,3-trifluoro-N-(3-(1-fluoro-2-hydroxyvinyl)cyclobutyl)-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 029

[0462] The synthetic method is the same as Example 15, and the starting material compound 018a is replaced by compound 029a to produce the target compound 029.

[0463] MS: (ESI, m / z): 543.1 [M+H] +

[0464] 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.31 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.64 (s, 2H), 7.57 - 7.52 (m, 2H), 7.20 - 7.15 (m, 2H), 5.04 - 4.97 (m, 1H), 4.29 - 4.22 (m, 1H), 3.90 - 3.81 (m, 2H), 2.99 - 2.78 (m, 3H), 2.70 - 2.64 (m, 1H).

[0465] Example 32

[0466] 2-Fluoro-2-(3-((S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanamido)cyclobutylidenyl)acetic acid 030

[0467] The synthetic method is the same as Example 15, and the starting material compound 018a is replaced by compound 030a to produce the target compound 030.

[0468] MS: (ESI, m / z): 557.1 [M+H] +

[0469] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.90 (t, J = 6.3 Hz, 1H), 8.48 (s, 3H), 8.11 (d, J = 6.7 Hz, 1H), 7.80 - 7.42 (m, 4H), 7.24 - 6.98 (m, 2H), 4.30 - 4.20 (m, 1H), 3.28 - 3.16 (m, 1H), 3.04 - 2.67 (m, 3H).

[0470] Example 33

[0471] (S)-1-(6-(3-(2,2-diethylhydrazino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea 031

[0472] Step 1. Synthesis of compound 031

[0473] To a solution of 001g (40 mg, 0.093 mmol) in N,N-dimethylformamide (2 mL) was added 1,1-diethylphenylhydrazine 031a (17.16 mg, 0.14 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (26.74 mg, 0.14 mmol) and 1- hydroxybenzotriazole (18.85 mg, 0.14 mmol), the reaction was stirred at room temperature for 5 min, ethyldiisopropylamine (36.06 mg, 0.28 mmol) was added, the reaction was continued to stir at room temperature for 1 h. The reaction was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), dried, filtered, rotary evaporated, the obtained residue was purified by high performance liquid, conditions as follows (column specification: Waters 2767 / QDA Column: Pursuit XRs C18 21.2*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 46%~51% B; detection wavelength: 254 nm / 220 nm), to give the target compound 031 (1.86 mg, yield: 3.92%).

[0474] LCMS: (ESI, m / z): 500.2 [M+H] +

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.75 (s, 1H), 7.71 - 7.62 (m, 2H), 7.57 - 7.52 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 2.66 (q, J = 7.0 Hz, 4H), 0.84 (d, J = 7.1 Hz, 6H).

[0476] Example 34

[0477] (S)-1-(6-(3-(2-ethylhydrazino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol- 2-yl)-3-(4-fluorophenyl)urea 032

[0478] The target compound 032 was prepared by the same method as in Example 33, using compound 032a instead of compound 031a.

[0479] MS: (ESI, m / z): 472.1 [M+H] +

[0480] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.62 (s, 1H), 9.18 (s, 1H), 8.16 (s, 1H), 7.79 - 7.62 (m, 3H), 7.59 - 7.46 (m, 2H), 7.18 (t, J = 8.6 Hz, 2H), 4.90 (s, 1H), 2.74 - 2.67 (m, 2H), 0.92 (t, J = 7.1 Hz, 3H).

[0481] Example 35

[0482] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-methoxypropanamide 033

[0483] The target compound 033 was prepared according to the similar method of Example 33, by replacing the starting material compound 031a with compound 033a.

[0484] MS: (ESI, m / z): 459.1 [M+H] +

[0485] 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 2H), 9.30 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.67 (s, 2H), 7.57 - 7.51 (m, 2H), 7.21 - 7.14 (m, 2H), 3.56 (s, 3H).

[0486] Example 36

[0487] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-((1s,3R)-3-(methylsulfonamido)cyclobutyl)propanamide 034

[0488] The target compound 034 was prepared according to the similar method of Example 33, by replacing the starting material compound 031a with compound 034a.

[0489] MS: (ESI, m / z): 576.1 [M+H] +

[0490] 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.30 (s, 1H), 8.29 (d, J = 7.1 Hz, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.70 - 7.60 (m, 2H), 7.59 - 7.50 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 8.9 Hz, 2H), 3.92 - 3.80 (m, 1H), 3.50 - 3.42 (m, 1H), 2.82 (s, 3H), 2.64 - 2.58 (m, 2H), 2.05 - 1.96 (m, 1H), 1.94 - 1.83 (m, 1H).

[0491] Example 37

[0492] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-((1r,3S)-3-(methylsulfonamido)cyclobutyl)propanamide 035

[0493] The target compound 035 was prepared by the same method as in Example 33, using compound 035a instead of compound 031a.

[0494] LCMS: (ESI, m / z): 576.2 [M+H] +

[0495] 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.66 (s, 1H), 8.50 (d, J = 7.2 Hz, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.62 (s, 1H), 7.58 - 7.53 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.29 - 4.20 (m, 1H), 3.95 - 3.86 (m, 1H), 2.81 (s, 3H), 2.41 - 2.34 (m, 1H), 2.30 - 2.16 (m, 3H).

[0496] Example 38

[0497] (S)-N-((1s,3R)-3-(cyanomethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 036

[0498] The synthetic method is the same as Example 33, except that the raw material compound 031a is replaced by compound 036a to give the target compound 036.

[0499] MS: (ESI, m / z): 522.1 [M+H] +

[0500] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.45 (s, 1H), 8.40 - 8.30 (m, 1H), 8.14 (s, 1H), 7.82 (s, 1H), 7.69 - 7.60 (m, 2H), 7.58 - 7.50 (m, 2H), 7.28 - 7.09 (m, 2H), 4.20 - 4.01 (m, 1H), 2.57 (d, J = 6.6 Hz, 2H), 2.40 - 2.19 (m, 3H), 1.91 - 1.81 (m, 1H), 1.79 - 1.68 (m, 1H).

[0501] Example 39

[0502] (2S)-N-(3-ethenylcyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 037

[0503] The synthetic method is the same as Example 15, except that the raw material compound 013a is replaced by compound 037a to give the target compound 037.

[0504] MS: (ESI, m / z): 509.1 [M+H] +

[0505] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.25 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.73 - 7.60 (m, 2H), 7.59 - 7.46 (m, 2H), 7.18 (t, J = 8.7 Hz, 2H), 5.21 - 5.07 (m, 1H), 4.24 - 4.15 (m, 1H), 2.90 - 2.72 (m, 4H), 1.49 - 1.40 (m, 3H).

[0506] Example 40

[0507] (2S)-3,3,3-trifluoro-N-((3-(fluoromethenyl)cyclobutyl)methyl)-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 038

[0508] The synthetic method is the same as Example 15, and the starting material compound 013a is replaced by compound 038a to produce the target compound 038.

[0509] MS: (ESI, m / z): 527.2 [M+H] +

[0510] 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.51 (s, 1H), 8.34 (t, J = 6.1 Hz, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.64 (s, 2H), 7.58 - 7.48 (m, 2H), 7.21 - 7.13 (m, 2H), 6.76 - 6.42 (m, 1H), 3.25 - 3.16 (m, 2H), 2.66 - 2.55 (m, 3H), 2.37 - 2.28 (m, 2H).

[0511] Example 41

[0512] N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluoro-2-methylphenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 039

[0513] The synthetic method is the same as Example 21, and the starting material compound 019a is replaced by compound 039a to produce the target compound 039.

[0514] MS: (ESI, m / z): 544.9 [M+H] +

[0515] 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.51 (s, 1H), 8.34 (t, J = 6.1 Hz, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.64 (s, 2H), 7.58 - 7.48 (m, 2H), 7.21 - 7.13 (m, 2H), 6.76 - 6.42 (m, 1H), 3.25 - 3.16 (m, 2H), 2.66 - 2.55 (m, 3H), 2.37 - 2.28 (m, 2H).

[0516] Example 42

[0517] (S)-N-((1r,3S)-3-(cyanomethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide040

[0518] The target compound 040 was obtained by the synthetic method similar to Example 33, by replacing the starting material compound 031a with compound 040a.

[0519] MS: (ESI, m / z): 522.1 [M+H] + , RT (min): 1.719

[0520] 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.69 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.62 (s, 2H), 7.58 - 7.53 (m, 2H), 7.19 - 7.13 (m, 2H), 4.46 - 4.36 (m, 1H), 2.69 (d, J = 7.4 Hz, 2H), 2.47 - 2.41 (m, 1H), 2.33 - 2.26 (m, 1H), 2.22 - 2.14 (m, 1H), 2.05 - 1.92 (m, 2H).

[0521] Example 43

[0522] N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4- methoxybenzo[d]thiazol-6-yl)-2-hydroxypropanamide041

[0523] The target compound 041 was obtained by the synthetic method similar to Example 20, by replacing the starting material compound 018a with compound 041a.

[0524] MS: (ESI, m / z): 561.2 [M+H] +

[0525] 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.26 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.56 - 7.49 (m, 2H), 7.23 (s, 1H), 7.20 - 7.14 (m, 2H), 4.43 - 4.30 (m, 1H), 3.90 (s, 3H), 2.98 - 2.80 (m, 3H), 2.73 - 2.66 (m, 1H).

[0526] Example 44

[0527] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4- hydroxybenzo[d]thiazol-6-yl)-2-hydroxypropanamide 042

[0528] The target compound 042 was prepared by the same method as Example 20, using compound 018a instead of compound 018b.

[0529] MS: (ESI, m / z): 547.1 [M+H] +

[0530] 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.21 (s, 1H), 8.65 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.57 - 7.51 (m, 3H), 7.18 - 7.12 (m, 2H), 7.11 (s, 1H), 4.39 - 4.32 (m, 1H), 2.97 - 2.82 (m, 3H), 2.76 - 2.69 (m, 1H).

[0531] Example 45

[0532] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N- methoxy-N-methylpropanamide 043

[0533] First Step Synthesis of compound 043

[0534] Compound 043 (60.0 mg, yield 29.05%) was obtained as a white solid by the following purification condition (column specification: Waters 2767 / QDA Column: Pursuit XRs 10C18 21.2*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 51%~56% B; detection wavelength: 254 nm / 214 nm).

[0535] MS: (ESI, m / z): 473.1 [M+H] +

[0536] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.21 (s, 1H), 8.02 (s, 1H), 7.76 - 7.62 (m, 1H), 7.61 - 7.49 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 3.32 (s, 3H), 3.01 (s, 3H).

[0537] Example 46

[0538] (S)-N-(1-(cyanomethyl)azetidin-3-yl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 044

[0539] First Step Synthesis of compound 044b (tert-butyl (1-(cyanomethyl)azetidin-3-yl) carbonate)

[0540] To a solution of 3-N-tert-butoxycarbonylaminocyclobutane (450 mg, 2.62 mmol, 044a) in acetonitrile (5 mL) was added chloroacetonitrile (216 mg, 2.87 mmol) and N,N-diisopropylethylamine (676 mg, 5.24 mmol) at 80 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated to give a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 40%~70%) to give the target compound 044b (320 mg, yield 58.0%) as a colorless liquid.

[0541] MS: (ESI, m / z): 212.2 [M+H] +

[0542] Second Step Synthesis of compound 044c (2-(3-aminooxazetidin-1-yl)acetonitrile trifluoroacetate)

[0543] To a solution of 044b (100 mg, 0.47 mmol,) in DCM (2 mL) was added 4M hydrochloric acid dioxane (2 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude product 044c, which was used directly for the next step without purification.

[0544] MS: (ESI, m / z): 112.2 [M+H] +

[0545] Third Step Synthesis of compound 044 (N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(2,4- difluorophenyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide)

[0546] To a solution of compound 001g (30 mg, 0.07 mmol), EDACI (20.13 mg, 0.11 mmol), 024c (31.38 mg, 0.14 mmol) and HOBt (14.19 mg, 0.11 mmol) in DMF (2 mL) was added DIEA (27.14 mg, 0.21 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude product, which was purified by reverse phase preparative chromatography (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 61% B; detection wavelength: 254 nm / 220 nm) to give the target compound 044 (2.53 mg, yield 6.93%).

[0547] MS: (ESI, m / z): 523.2 [M+H] +

[0548] 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 9.92 (s, 1H), 8.67 (d, J = 6.5 Hz, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.64 - 7.55 (m, 4H), 7.18 - 7.13 (m, 2H), 4.34 - 4.19 (m, 1H), 3.60 (s, 2H), 3.56 - 3.52 (m, 1H), 3.49 - 3.45 (m, 1H), 3.18 (t, J = 6.9 Hz, 1H), 3.11 (t, J = 6.9 Hz, 1H).

[0549] Example 47

[0550] (R)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)- 6,8-dihydroisobenzo[furan-4,5-d]thiazol-5-yl)-2-hydroxypropanamide 045-A

[0551] Synthesis of compound 045b (3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-6,8- dihydroisobenzo[furan-4,5-d]thiazol-5-yl)-2-hydroxypropanoic acid ethyl ester)

[0552] To ethyl 2-(2-amino-6,8-dihydroisobenzo[furan-4,5-d]thiazol-5-yl)-3,3,3-trifluoro-2- hydroxypropanoate (690 mg, 1.90 mmol, 045a) in N,N-dimethylformamide (10 mL), 1-fluoro-4-isocyanobenzene (391 mg, 2.85 mmol) was added dropwise slowly, the reaction was stirred at room temperature for 2 hours. To the reaction, water (50 mL) was added to dilute, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel normal phase chromatography column (petroleum ether: ethyl acetate = 1:1) to give the target product 045b (670 mg, yield 70.44%) as a light yellow solid.

[0553] LCMS: (ESI, m / z): 500.2 [M+H] +

[0554] Synthesis of compound 045c ((R)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-6,8- dihydroisobenzo[furan-4,5-d]thiazol-5-yl)-2-hydroxypropanoate)

[0555] Chiral SFC separation of 045b (670 mg, 1.34 mmol) was performed under the following conditions (column specifications: 250*30 mm 10 pm; mobile phase A: supercritical CO2, mobile phase B: isopropyl alcohol (+0.1% 7.0 mol / L ammonia methanol solution); flow rate: 140 mL / min; detection wavelength: UV 214 nm; A:B = 70:30; flow rate: 140 mL / min; column temperature: RT; injection volume: 5 mL; cycle time: 3.2 min; solvent: methanol (200 mL), retention time (min): 2.80-3.60; to obtain crude 045c (290 mg, purity: 96%). The crude 045c was purified by silica gel normal phase column (dichloromethane:methanol = 20:1) to obtain the target product (235 mg, yield 24.71%)

[0556] 045c:

[0557] LCMS: (ESI, m / z): 500.2 [M+H] + , RT (min): 2.80-3.60

[0558] 1 H NMR (400 MHz, DMSO-d6) d 11.17 (s, 1H), 9.11 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.57-7.48 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 5.34-5.11 (m, 4H), 4.38-4.25 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0559] Synthesis of compound 045d ((R)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)- 6,8-dihydroisobenzo[furan-4,5-d]thiazol-5-yl)-2-hydroxypropanoic acid)

[0560] To the solution of compound 045c (40 mg, 0.08 mmol) in methanol (4 mL), lithium hydroxide (19 mg, 0.8 mmol) and water (1 mL) were added slowly, and the reaction was stirred at 50 degrees Celsius for 1 hour. The reaction was concentrated under vacuum, the concentrate was diluted with water (20 mL), 1N hydrochloric acid aqueous solution was slowly added dropwise to adjust PH = 3-4, extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product 045d (35 mg, yield 92.71%) as a yellowish solid crude. Directly used in the next step. LCMS: (ESI, m / z): 472.1 [M+H] +

[0561] Fourth Step Synthesis of Compound 045-A

[0562] To 045d (35 mg, 0.075 mmol) in N,N-dimethylformamide (3 mL) was added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22 mg, 0.0.11 mmol) and 1- hydroxybenzotriazole (15 mg, 0.11 mmol) under nitrogen atmosphere. The reaction was stirred at room temperature for 10 minutes under nitrogen atmosphere. To the reaction was added 3- (difluoromethyl)cyclobutane-1 -amine hydrochloride (14 mg, 0.089 mmol) and N,N- diisopropylethylamine (27 mg, 0.22 mmol) and the reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. To the reaction was added water (30 mL) and diluted, extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by high performance liquid chromatography under the following conditions (column specification: Sunfire C18,19*250mm,10um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 62%~67% B; detection wavelength: 254 nm / 220 nm) to give the target compound 045-A (3.16 mg, yield 7.43%).

[0563] LCMS: (ESI, m / z): 573.2 [M+H] +

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.26 (s, 1H), 8.74 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.56 - 7.50 (m, 2H), 7.20 - 7.14 (m, 2H), 5.27 - 5.16 (m, 4H), 4.43 - 4.33 (m, 1H), 2.97 - 2.88 (m, 2H), 2.86 - 2.79 (m, 1H), 2.76 - 2.69 (m, 1H).

[0565] Example 48

[0566] (S)-N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)- 6,8-dihydroisobenzo[furan-5-yl)-2-hydroxypropanamide 045-B

[0567] LCMS: (ESI, m / z): 573.2 [M+H] +

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.50 (s, 1H), 8.74 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 7.86 (s, 1H), 7.58 - 7.51 (m, 2H), 7.23 - 7.13 (m, 2H), 5.27 - 5.16 (m, 4H), 4.43 - 4.33 (m, 1H), 2.97 - 2.89 (m, 2H), 2.86 - 2.79 (m, 1H), 2.76 - 2.69 (m, 1H).

[0569] Example 49

[0570] N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(3,4-dimethylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide 046

[0571] (S)-N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(3,4-dimethylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide

[0572] (R)-N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(3,4-dimethylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide

[0573] First step synthesis of compound 046b (4-iodo-3-methylisothiazol-5-amine)

[0574] The 5-amino-3-methyl-isothiazole hydrochloride (7.295 g, 48.43 mmol, 046a) was dissolved in N,N-dimethylformamide (100 mL) at room temperature, and N-iodosuccinimide (11.99 g, 53.27 mmol) was added. The reaction solution was stirred at 25 degrees overnight. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (60 mL x 3), the organic phase was combined and washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 ~ 0:100) to give the target compound 046b (9.23 g, yield 79.39%) as a transparent oil.

[0575] MS: (ESI, m / z): 241.0 [M+H] +

[0576] Second Step Synthesis of compound 046c (tert-butyl (4-iodo-3-methylisothiazol-5- yl)carbamate)

[0577] Compound 046b (9.3 g, 38.74 mmol) and triethylamine (7.84 g, 77.48 mmol) were dissolved in dichloromethane (80 mL) at room temperature, di-tert-butyl dicarbonate (10.15 g, 46.49 mmol) and 4-dimethylaminopyridine (0.47 g, 3.87 mmol) were added. The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to get the crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 ~ 0:100) to get the target compound 046c (7.3 g, yield 55.39%) as a yellow solid.

[0578] MS: (ESI, m / z): 341.0 [M+H] +

[0579] Third Step Synthesis of compound 046d (tert-butyl (3,4-dimethylisothiazol-5- yl)carbamate)

[0580] Compound 046c (2.5 g, 7.35 mmol) and methylboronic acid (0.88 g, 14.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (537.80 mg, 0.73 mmol) and potassium carbonate (3.05 g, 22.05 mmol) were dissolved in 1,4-dioxane (30 mL) and water (3 mL) at room temperature, replaced with nitrogen for three times, the reaction solution was stirred at 90 degrees overnight. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (60 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to get the crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 ~ 1:1) to get the target compound 046d (1.0 g, yield 35.76%) as a yellow solid

[0581] MS: (ESI, m / z): 229.1 [M+H] +

[0582] Fourth Step Synthesis of compound 046e (3,4-dimethylisothiazol-5-amine)

[0583] Compound 046d (900 mg, 3.94 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (20 mL) was added at room temperature. The reaction was stirred at room temperature for 16 hours. The reaction was concentrated, the pH value was adjusted to 11 with aqueous sodium bicarbonate solution, and extracted with ethyl acetate (80 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound 046e (500 mg, 98.94%) as a yellow solid.

[0584] MS: (ESI, m / z): 129.1 [M+H] +

[0585] Fifth step Synthesis of compound 046f (4-nitrophenyl (3,4-dimethylisothiazol-5-yl)carbamate)

[0586] Compound 046e (450 mg, 3.51 mmol) and pyridine (832.92 mg, 10.53 mmol) were dissolved in tetrahydrofuran (20 mL) at room temperature, and p-nitrophenyl chloroformate (707.48 mg, 3.51 mmol) was added at 0 degrees. The reaction was stirred at room temperature for 1 hour. TLC showed that the reaction was complete, and it was directly used in the next step.

[0587] Sixth step Synthesis of compound 046g (2-(2-(3-(3,4-dimethylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid ethyl ester)

[0588] Pyridine (555.28 mg, 7.02 mmol) and 2-(2-amino benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid ethyl ester (505.90 mg, 1.58 mmol) were added to the above reaction solution at room temperature, and the reaction was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (80 mL x 3), the organic phase was combined, washed with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 to 0:100) and reverse phase C18 (0.01% FA) to obtain the target compound 046g (290 mg, yield 17.42%) as a yellow oil.

[0589] MS: (ESI, m / z): 475.2 [M+H] +

[0590] Seventh step Synthesis of compound 046h (2-(2-(3-(3,4-dimethylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid)

[0591] Compound 046g (150 mg, 0.32 mmol) and lithium hydroxide (76.64 mg, 3.2 mmol) were dissolved in methanol (20 mL) and water (10 mL) at room temperature, and the reaction solution was stirred at 50 °C for 1 h. The reaction solution was concentrated, the pH was adjusted to 4 with 1 N hydrochloric acid solution, and extracted with ethyl acetate (60 mL x 3). The organic phase was combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound 046h (208 mg, yield 92.11%) as a white solid.

[0592] MS: (ESI, m / z): 447.0 [M+H] +

[0593] Eighth step Synthesis of compound 046 (N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(3,4-dimethylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide)

[0594] Compound 046h (240 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (207.04 mg, 1.08 mmol), and 1-hydroxybenzotriazole (145.93 mg, 1.08 mmol) were dissolved in N,N-dimethylformamide (6 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 min. 3-(Difluoromethyl)cyclobutylamine hydrochloride (126.00 mg, 0.81 mmol) and N,N-diisopropylethylamine (348.95 mg, 2.7 mmol) were added, and the reaction solution was stirred at room temperature for 2 h. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (60 mL x 3), and the organic phase was combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 ~ 0:100) and high performance liquid chromatography, under the following conditions (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 52% ~ 55% B, detection wavelength: 254 nm / 214 nm) to give the target compound 046 (67.13 mg, 22.81%).

[0595] 046

[0596] MS: (ESI, m / z): 547.8 [M+H] +

[0597] 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.39 (s, 1H), 8.72 (d, J = 7.6 Hz, 1H), 8.21 - 8.11 (m, 1H), 7.91 (s, 1H), 7.72 - 7.56 (m, 2H), 4.41 - 4.30 (m, 1H), 2.99 - 2.80 (m, 3H), 2.74 - 2.67 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H).

[0598] Ninth Step Synthesis of compounds 046-A and 046-B

[0599] Compound 046 (67.13 mg, 0.12 mmol) was separated by SFC, conditions as follows (System: SHIMADZU LC-20AP; Column: REGIS (S, S) WHELK-O1; Column size: 250*40 mm 10 pm; Mobile phase: A n-hexane, mobile phase B: ethanol (+0.1% 7.0 mol / L amine methanol solution); A:B = 80:20; Wavelength: 254 nm; Flow rate: 80 mL / min; Column temperature: RT; Back pressure: 100 bar; Injection volume: 1.0 mL; Cycle time: 17 min; Solvents: n-hexane: Distilled grade, ethanol: Distilled grade), the first peak, gave crude compound 046-A and purified by high performance liquid, conditions as follows (Column size: Waters 2767 / QDA Column: Welch Ultimate XB-Phenyl 21.2*250mm*10 pm; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; Flow rate: 20 mL / min; Elution gradient: 52% B, 25 min; Detection wavelength: 254 nm / 214 nm) to give 046-A (9.15 mg, 3.11%). The second peak, gave crude compound 046-B and purified by high performance liquid, conditions as follows (Column size: Waters 2767 / QDA Column: Welch Ultimate XB-Phenyl 21.2*250mm*10 pm; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; Flow rate: 20 mL / min; Elution gradient: 52% B, 25 min; Detection wavelength: 254 nm / 214 nm) to give 046-B (10.58 mg, 3.59%).

[0600] 046-A

[0601] MS: (ESI, m / z): 548.1 [M+H] + , RT (min): 19.5-22.08

[0602] 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.72 (d, J = 7.5 Hz, 1H), 8.23 - 8.10 (m, 1H), 8.01 - 7.82 (m, 1H), 7.74 - 7.55 (m, 2H), 4.42 - 4.28 (m, 1H), 2.97 - 2.77 (m, 3H), 2.75 - 2.67 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H).

[0603] 046-B

[0604] MS: (ESI, m / z): 548.0 [M+H] + , RT (min): 23.28 - 28.33

[0605] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.22 - 8.10 (m, 1H), 7.91 (s, 1H), 7.74 - 7.55 (m, 2H), 4.42 - 4.30 (m, 1H), 3.03 - 2.77 (m, 3H), 2.75 - 2.67 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H).

[0606] Example 50

[0607] N-(3-(Difluoromethylidene)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa- 1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 047

[0608] (S)-N-(3-(Difluoromethylidene)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa- 1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0609] (R)-N-(3-(Difluoromethylidene)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa- 1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0610] First step synthesis of compound 047b (N-(5-bromodicyclo[4.2.0]octa- 1(6),2,4-trien-2-yl)-1,1-diphenylmethanimine)

[0611] To a solution of 2,5-dibromobicyclo[4.2.0]octa-l(6),2,4-triene (8 g, 30.54 mmol, 047a) in toluene (100 mL) was added diphenylmethanimine (5534.76 mg, 30.54 mmol), Pd2(dba)3(2796.61 mg, 3.05 mmol), BINAP (3803.27 mg, 6.11 mmol) and sodium tert-butoxide (5869.79 mg, 6.11 mmol) and stirred at 100 °C for 2 h under nitrogen protection. The reaction was concentrated, diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined and washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target product 047b (8 g, yield: 72.31%) as a yellow solid.

[0612] MS: (ESI, m / z): 364.0 [M+H] +

[0613] Second Step: Synthesis of compound 047c (5-bromobicyclo[4.2.0]octa-l(6),2,4-triene-2-amine)

[0614] 047b (8 g, 22.08 mmol) was added to a solution of 4 M hydrochloric acid in 1,4-dioxane (80 mL) and water (4 mL) at room temperature and stirred at room temperature for 1 h. The reaction was diluted with saturated aqueous ammonium bicarbonate solution (50 mL) and extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give the target product 047c (3.2 g, yield: 73.16%) as a yellow oil.

[0615] MS: (ESI, m / z): 239.0 [M+41+H] +

[0616] Third Step: Synthesis of compound 047d (2-bromo-5-fluorobicyclo[4.2.0]octa-l(6),2,4-triene)

[0617] To 047c (3200 mg, 16.16 mmol) was added hydrogen fluoride pyridine (20 mL), 0 degree Celsius, then isopentylnitrite (3.26 mL, 24.24 mmol) was slowly added dropwise into the reaction solution, and the reaction was carried out at room temperature for 1 hour. To the reaction solution was added saturated aqueous ammonium bicarbonate solution (100 mL) for dilution, and extraction was carried out with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 047d (2700 mg, yield: 83.12%) as a yellow oil.

[0618] MS: (ESI, m / z): 200.1 [M] +

[0619] Fourth step Synthesis of compound 047e (N-(5-fluorobicyclo[4.2.0]octa-1(6),2,4- trien-2-yl)-1,1-diphenylmethanimine)

[0620] To a solution of 047d (2.7 g, 13.43 mmol) in toluene (80 mL) was added diphenylmethanimine (2920.70 mg, 16.12 mmol), Pd2(dba)3 (1229.81 mg, 1.34 mmol), BINAP (1672.49 mg, 2.69 mmol), and sodium tert-butoxide (2581.25 mg, 26.86 mmol) at room temperature, and the reaction was carried out at 100 degree Celsius for 2 hours under nitrogen protection. To the reaction solution was added water (100 mL) for dilution, and extraction was carried out with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target product 047e (3500 mg, yield: 86.48%) as a yellow solid.

[0621] MS: (ESI, m / z): 302.1 [M+H] +

[0622] Fifth step Synthesis of compound 047f (5-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-2-amine)

[0623] To a solution of 047e (3500 mg, 11.61 mmol) in water (1 mL) was added 4M hydrochloric acid in 1,4-dioxane (20 mL) at room temperature and stirred for 1 hour at room temperature. To the reaction was added saturated aqueous ammonium bicarbonate solution (50 mL) and diluted, extracted with ethyl acetate (20 mL x 3), combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give the target product (1500 mg, yield: 94.17%) as yellow oil.

[0624] MS: (ESI, m / z): 138.2 [M+H] +

[0625] Synthesis of compound 047g (3,3,3-trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa-1(6),2,4- trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid ethyl ester)

[0626] To a solution of 047f (100 mg, 0.73 mmol) in dichloromethane was added to a solution of triphosgene (216.63 mg, 0.73 mmol) in dichloromethane (3 mL) at 0 °C and reacted for 0.5 hours, then added DIEA (283.04 mg, 2.19 mmol) and reacted for 0.5 hours at room temperature, then concentrated, dissolved in tetrahydrofuran (3 mL), added 2-(2-amino-1,3-benzothiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid ethyl ester (173.02 mg, 0.54 mmol) and reacted for 1 hour at room temperature. Diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0%~40%) to give the target compound 047g (180 mg, yield: 51.07%) as yellow oil.

[0627] MS: (ESI, m / z): 484.1 [M+H] +

[0628] Synthesis of compound 047h (3,3,3-trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa-1(6),2,4- trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid)

[0629] Compound 047g (180 mg, 0.37 mmol) and lithium hydroxide (88.61 mg, 3.7 mmol) were dissolved in methanol (2 mL) and water (1 mL) at room temperature, and the reaction solution was stirred at 50 °C for 2 h. The reaction solution was concentrated, the pH was adjusted to 4 with 1 N hydrochloric acid solution, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound 047h (160 mg, yield: 94.37%) as a yellow oil.

[0630] MS: (ESI, m / z): 456.1 [M+H] +

[0631] Eighth Step Synthesis of compound 047 (N-(3-(difluoromethyl)cyclobutyl)-3,3,3- trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol- 6-yl)-2-hydroxypropanamide)

[0632] 3,3,3-trifluoro-2-(2-(3-(5-fluorodicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol- 6-yl)-2-hydroxypropanoic acid (160 mg, 0.35 mmol), 3-(difluoromethyl)cyclobutane-1- amine hydrochloride (81.67 mg, 0.52 mmol), EDCI (100.64 mg, 0.52 mmol), and HOBt (70.94 mg, 0.52 mmol) were added to DMF (2 mL), and DIEA (135.70 mg, 1.05 mmol) was added to the reaction solution, which was reacted at room temperature for 2 h. The reaction solution was concentrated to give a crude product, which was purified by C18 (0.1% FA) reverse phase to give the target compound 047 (110 mg, yield 56.26%).

[0633] MS: (ESI, m / z): 557.4 [M+H] +

[0634] Ninth Step Synthesis of compounds 047-A and 047-B

[0635] Compound 047 (110 mg, 0.197 mmol) was separated by chiral SFC under the following conditions (column specifications: 250*30mm 10μm; mobile phase A: supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol solution); flow rate: 140 mL / min; detection wavelength: UV 214 nm; A:B = 60:40; flow rate: 140 mL / min; column temperature: RT; injection volume: 2 mL; cycle time: 7.2 min; solvent: methanol (8 mL), to obtain crude product 047-A and crude product 047-B. Crude product 047-A was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 63% B ~ 63% B, 16 min; detection wavelength: 254 nm / 220 nm), to obtain target compound 047-A (15.80 mg, yield 14.42%). Crude product 047-B was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 64% B ~ 65% B, 16 min; detection wavelength: 254 nm / 220 nm), to obtain target compound 047-B (15.75 mg, yield 14.42%).

[0636] 047-A

[0637] LCMS: (ESI, m / z): 557.1 [M+H] + , RT (min): 4.55-6.78

[0638] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.10 (s, 1H), 8.72 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.72 - 7.58 (m, 2H), 7.35 (dd, J = 9.0, 3.6 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 4.44 - 4.27 (m, 1H), 3.26 - 3.19 (m, 2H), 3.16 - 3.10 (m, 2H), 2.98 - 2.82 (m, 3H), 2.77 - 2.69 (m, 1H).

[0639] 047-B

[0640] LCMS: (ESI, m / z): 557.1 [M+H] + , RT (min): 7.25-10.20

[0641] 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.07 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.76 - 7.55 (m, 2H), 7.35 (dd, J = 9.0, 3.7 Hz, 1H), 6.96 (t, J = 8.5 Hz, 1H), 4.45 - 4.24 (m, 1H), 3.27 - 3.22 (m, 2H), 3.18 - 3.11 (m, 2H), 3.00 - 2.81 (m, 3H), 2.72 - 2.66 (m, 1H).

[0642] Example 51

[0643] (S)-1-(6-(3-(3-(cyanomethyl)azetidin-1-yl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea048

[0644] The target compound 048 was prepared according to the similar method of Example 14, by replacing the starting material compound 012a with compound 048a.

[0645] LCMS: (ESI, m / z): 508.2 [M+H] +

[0646] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.28 (s, 1H), 8.07 (d, J = 13.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 - 7.61 (m, 1H), 7.57 - 7.50 (m, 3H), 7.17 (t, J = 8.9 Hz, 2H), 4.36 (t, J = 9.2 Hz, 1H), 4.11 - 3.97 (m, 2H), 3.76 - 3.53 (m, 2H), 3.23 - 3.12 (m, 1H), 2.92 - 2.60 (m, 3H).

[0647] Example 52

[0648] (S)-1-(6-(3-(3-(difluoromethoxy)azetidin-1-yl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea049

[0649] The target compound 049 was prepared according to the similar method of Example 14, by replacing the starting material compound 012a with compound 049a.

[0650] LCMS: (ESI, m / z): 535.2 [M+H] +

[0651] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.25 (s, 1H), 8.20 - 8.03 (m, 1H), 7.96 - 7.84 (m, 1H), 7.75 - 7.63 (m, 1H), 7.61 - 7.49 (m, 3H), 7.18 (t, J = 8.8 Hz, 2H), 6.91 - 6.37 (m, 1H), 4.93 - 4.73 (m, 1H), 4.60 - 4.23 (m, 2H), 3.90 - 3.80 (m, 1.5H), 3.41 - 3.37 (m, 0.5H).

[0652] Example 53

[0653] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(6-fluoropyridin-3- yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 050

[0654] The target compound 050 was prepared by the same method as Example 21, by replacing the raw material compound 019a with compound 050a.

[0655] MS: (ESI, m / z): 565.2 [M+H] +

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.43 (s, 1H), 8.72 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 8.26 - 8.04 (m, 2H), 7.90 (s, 1H), 7.81 - 7.50 (m, 2H), 7.26 - 7.11 (m, 1H), 4.48 - 4.22 (m, 1H), 3.02 - 2.68 (m, 4H).

[0657] Example 54

[0658] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(5-fluoropyridin-2- yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 051

[0659] The synthetic method is the same as Example 21, and the raw material compound 019a is replaced by compound 051a to give the target compound 051.

[0660] MS: (ESI, m / z): 532.1 [M+H] +

[0661] 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.76 (d, J = 7.7 Hz, 1H), 8.43 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.14 (s, 1H), 8.03 - 7.92 (m, 1H), 7.92 - 7.83 (m, 1H), 7.80 - 7.74 (m, 1H), 7.68 - 7.60 (m, 2H), 4.40 - 4.33 (m, 1H), 2.95 - 2.84 (m, 3H), 2.76 - 2.71 (m, 1H).

[0662] Example 55

[0663] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(pyridin-3- yl)ureido)benzo[d]thiazol-6-yl)propanamide 053

[0664] The synthetic method is the same as Example 21, and the raw material compound 019a is replaced by compound 052a to give the target compound 052.

[0665] MS: (ESI, m / z): 515.2 [M+H] +

[0666] 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.67 (s, 1H), 9.00 (s, 2H), 8.85 (s, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.68 - 7.54 (m, 2H), 4.58 - 4.19 (m, 1H), 3.01 - 2.86 (m, 2H), 2.84 - 2.70 (m, 2H).

[0667] Example 56

[0668] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(pyridin-3- yl)ureido)benzo[d]thiazol-6-yl)propanamide 053

[0669] The synthetic method is the same as in Example 21, and the starting material compound 019a is replaced by compound 053a to give the target compound 053.

[0670] MS: (ESI, m / z): 514.1 [M+H] +

[0671] 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.65 (s, 1H), 8.81 - 8.64 (m, 2H), 8.27 (dd, J = 4.7, 1.3 Hz, 1H), 8.16 (s, 1H), 8.06 - 7.99 (m, 1H), 7.90 (s, 1H), 7.70 - 7.59 (m, 2H), 7.42 - 7.31 (m, 1H), 4.41 - 4.30 (m, 1H), 2.99 - 2.79 (m, 3H), 2.75 - 2.67 (m, 1H).

[0672] Example 57

[0673] N-(3-(Difluoromethylidene)cyclobutyl)-2-(2-(3-(1,5-dimethyl-1H-pyrazol-4-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide 054

[0674] The synthetic method is the same as in Example 21, and the starting material compound 019a is replaced by compound 054a to give the target compound 054.

[0675] LCMS: (ESI, m / z): 531.3 [M+H] +

[0676] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.72 - 7.58 (m, 2H), 7.46 (s, 1H), 4.42 - 4.29 (m, 1H), 3.71 (s, 3H), 2.96 - 2.84 (m, 2H), 2.84 - 2.79 (m, 1H), 2.77 - 2.69 (m, 1H), 2.17 (s, 3H).

[0677] Example 58

[0678] N-(3-(difluoromethyl)cyclobutyl)-2-(2-(3-(1,3-dimethyl-1H-pyrazol-4-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide 055

[0679] The target compound 055 was prepared according to the similar procedure as described in Example 21, using compound 055a instead of compound 019a.

[0680] LCMS: (ESI, m / z): 531.1 [M+H] +

[0681] 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.68 - 7.61 (m, 2H), 4.41 - 4.30 (m, 1H), 3.73 (s, 3H), 2.98 - 2.79 (m, 3H), 2.74 - 2.68 (m, 1H), 2.11 (s, 3H).

[0682] Example 59

[0683] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(5-methyl-1H-pyrazol-4-yl)ureido)benzo[d]thiazol-6-yl)propanamide 056

[0684] The target compound 056 was prepared according to the similar procedure as described in Example 21, using compound 056a instead of compound 019a.

[0685] LCMS: (ESI, m / z): 517.0 [M+H] +

[0686] 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.80 - 7.42 (m, 3H), 4.41 - 4.30 (m, 1H), 3.02 - 2.73 (m, 4H), 2.16 (s, 3H).

[0687] Example 60

[0688] 2-(2-(3-(1H-Indol-4-yl)ureido)benzo[d]thiazol-6-yl)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxypropanamide 057

[0689] The title compound 057 was obtained by the synthetic method similar to Example 21, by replacing the starting material compound 019a with compound 057a.

[0690] LCMS: (ESI, m / z): 503.0 [M+H] +

[0691] 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 11.24 (s, 1H), 9.13 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.78 - 7.52 (m, 4H), 4.40 - 4.31 (m, 1H), 2.98 - 2.83 (m, 3H), 2.74 - 2.69 (m, 1H).

[0692] Example 61

[0693] 3,3,3-Trifluoro-N-[(S,Z)-3-(fluoromethyl)cyclobutyl]-2-[2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl]-2-hydroxypropanamide 058

[0694] MS: (ESI, m / z): 531.3 [M+H] +

[0695] 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.15 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 8.10 - 8.00 (m, 1H), 7.86 (s, 1H), 7.69 - 7.63 (m, 2H), 7.41 - 7.32 (m, 1H), 7.17 - 7.07 (m, 1H), 6.79 - 6.54 (m, 1H), 4.41 - 4.20 (m, 1H), 2.97 - 2.86 (m, 2H), 2.83 - 2.67 (m, 2H).

[0696] Example 62

[0697] (S)-N-((1r,3S)-3-(diifluoromethoxy)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)-6-benzo[d]thiazolyl)-2-hydroxypropanamide 059

[0698] The target compound 059 was prepared according to the similar procedure as described in Example 33, by replacing compound 031a with compound 059a.

[0699] MS: (ESI, m / z): 549.1 [M+H] +

[0700] 1 H NMR (400 MHz, DMSO-d6) d 11.13 (s, 1H), 9.30 (s, 1H), 8.58 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.69 - 7.61 (m, 2H), 7.57 - 7.51 (m, 2H), 7.21 - 7.14 (m, 2H), 6.60 (t, J = 75.9 Hz, 1H), 4.74 - 4.67 (m, 1H), 4.38 - 4.29 (m, 1H), 2.43 - 2.29 (m, 4H).

[0701] Example 63

[0702] (S)-N-((1s,3R)-3-(diifluoromethoxy)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)-6-benzo[d]thiazolyl)-2-hydroxypropanamide 060

[0703] The target compound 060 was prepared according to the similar procedure as described in Example 33, by replacing compound 031a with compound 060a.

[0704] MS: (ESI, m / z): 549.2 [M+H] +

[0705] 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.24 (s, 1H), 8.52 (d, J = 7.9 Hz, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.74 - 7.61 (m, 2H), 7.58 - 7.51 (m, 2H), 7.21 - 7.15 (m, 2H), 6.59 (t, J = 75.7 Hz, 1H), 4.37 - 4.24 (m, 1H), 3.96 - 3.85 (m, 1H), 2.64 - 2.52 (m, 2H), 2.28 - 2.19 (m, 1H), 2.16 - 2.07 (m, 1H).

[0706] Example 64

[0707] (2S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-(3-(hydroxyimino)cyclobutyl)propanamide 061

[0708] The target compound 061 was prepared according to the similar method of Example 33, by replacing the starting material compound 031a with compound 061a.

[0709] MS: (ESI, m / z): 512.1 [M+H] +

[0710] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.29 (d, J = 4.9 Hz, 1H), 9.21 (s, 1H), 8.70 (d, J = 7.3 Hz, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.72 - 7.62 (m, 2H), 7.58 - 7.49 (m, 2H), 7.22 - 7.14 (m, 2H), 4.39 - 4.21 (m, 1H), 3.13 - 2.98 (m, 2H), 2.95 - 2.84 (m, 1H), 2.82 - 2.72 (m, 1H).

[0711] Example 65

[0712] N-(3-(difluoromethylidene)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3- phenylureido)benzo[d]thiazol-6-yl)propanamide 062

[0713] The target compound 062 was prepared according to the similar method of Example 21, by replacing the starting material compound 019a with compound 062a.

[0714] LCMS: (ESI, m / z): 513.2 [M+H] +

[0715] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.19 (s, 1H), 8.72 (d, J = 7.3 Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.71 - 7.63 (m, 2H), 7.56 - 7.50 (m, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.10 - 7.03 (m, 1H), 4.41 - 4.31 (m, 1H), 2.97 - 2.79 (m, 3H), 2.74 - 2.65 (m, 1H).

[0716] Example 66

[0717] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(pyridin-4- yl)ureido)benzo[d]thiazol-6-yl)propanamide 063

[0718] The target compound 063 was prepared by the same method as in Example 21, using compound 063a instead of compound 019a.

[0719] LCMS: (ESI, m / z): 487.3 [M+H] +

[0720] 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 5.4 Hz, 2H), 8.23 (s, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.64 (s, 2H), 7.55 (d, J = 6.1 Hz, 2H), 4.40 - 4.33 (m, 1H), 2.95 - 2.80 (m, 3H), 2.73 - 2.67 (m, 1H).

[0721] Example 67

[0722] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-((1r,3S)-3-(trifluoromethoxy)cyclobutyl)propanamide 064

[0723] The target compound 064 was prepared by the same method as in Example 33, using compound 064a instead of compound 031a.

[0724] MS: (ESI, m / z): 567.0 [M+H] +

[0725] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.25 (s, 1H), 8.67 (d, J = 6.3 Hz, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.71 - 7.60 (m, 2H), 7.59 - 7.50 (m, 2H), 7.24 - 7.12 (m, 2H), 5.06 - 4.88 (m, 1H), 4.42 - 4.31 (m, 1H), 2.47 - 2.30 (m, 4H).

[0726] Example 68

[0727] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-((1s,3R)-3-(trifluoromethoxy)cyclobutyl)propanamide 065

[0728] The target compound 065 was prepared by the same method as Example 33, by replacing the starting compound 031a with compound 065a.

[0729] MS: (ESI, m / z): 567.0 [M+H] +

[0730] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.22 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 7.85 (s, 1H), 7.75 - 7.60 (m, 2H), 7.58 - 7.50 (m, 2H), 7.21 - 7.14 (m, 2H), 4.58 - 4.51 (m, 1H), 4.01 - 3.89 (m, 1H), 2.68 - 2.56 (m, 2H), 2.41 - 2.32 (m, 1H), 2.30 - 2.21 (m, 1H).

[0731] Example 69

[0732] (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-(prop-2-yn-1-yl)propanamide 066

[0733] The synthetic method is the same as Example 33, and the starting material compound 031a is replaced by compound 066a to give the target compound 066.

[0734] MS: (ESI, m / z): 467.2 [M+H] +

[0735] 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.36 (s, 1H), 8.64 (t, J = 5.8 Hz, 1H), 8.14 (s, 1H), 7.90 (s, 1H), 7.66 (s, 2H), 7.60 - 7.51 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 3.87 (dd, J = 5.7, 2.3 Hz, 2H), 3.06 (t, J = 2.3 Hz, 1H).

[0736] Example 70

[0737] (S)-N-(but-2-yn-1-yl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)- 2-hydroxypropanamide 067

[0738] The synthetic method is the same as Example 33, and the starting material compound 031a is replaced by compound 067a to give the target compound 067.

[0739] MS: (ESI, m / z): 481.2 [M+H] +

[0740] 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.52 (t, J = 5.8 Hz, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.62 - 7.56 (m, 4H), 7.16 - 7.11 (m, 2H), 3.86 - 3.82 (m, 2H), 1.74 (t, J = 2.3 Hz, 3H).

[0741] Example 71

[0742] 1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea 068

[0743] (S)-1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea

[0744] (R)-1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea

[0745] First Step: Synthesis of compound 068b (2-(4-bromophenyl)-3,3,3-trifluoro-2-hydroxy-1- (1-methyl-1H-pyrazol-4-yl)propan-1-one)

[0746] To a solution of compound 1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-one (3.00 g, 11.86 mmol, 068a) in tetrahydrofuran (50 mL) under nitrogen atmosphere, 1-methyl-1H-pyrazole-4- carboxaldehyde (1.31 g, 11.86 mmol), pentacyclic phenylhydrazine triazole (0.26 g, 0.95 mmol) and DBU (0.29 g, 1.90 mmol) were added slowly in turn, and the reaction was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then purified by silica gel normal phase chromatography column (petroleum ether: ethyl acetate = 1:1) to obtain the target product 068b (1.40 g, yield 32.52%) as a light yellow solid.

[0747] Second Step: Synthesis of compound 068c (2-(4-((diphenylmethylene)amino)phenyl)-3,3,3- trifluoro-2-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)propan-1-one)

[0748] To a solution of 068b (1.40 g, 3.86 mmol) in 1,4-dioxane (30 mL) was added diphenylmethanamine (1.05 g, 5.79 mmol), tris(dibenzylideneacetone)dipalladium (0.35 g, 0.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.45 g, 0.77 mmol) and cesium carbonate (1.89 g, 5.79 mmol) sequentially under nitrogen atmosphere. The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give the target product 068c (650 mg, yield 36.38%) as a light yellow solid.

[0749] LCMS: (ESI, m / z): 464.2 [M+H] +

[0750] Step 3: Synthesis of compound 068d (2-(4-aminophenyl)-3,3,3-trifluoro-2-hydroxy-1- (1-methyl-1H-pyrazol-4-yl)propan-1-one)

[0751] To a solution of 068c (600 mg, 1.29 mmol) in 1,4-dioxane (10 mL) was added water (0.5 mL), hydrochloric acid in 1,4-dioxane (4 N, 20.00 mL, 80.00 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The concentrate was diluted with water (30 mL) and quenched with saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by C18 reverse phase (water 0.1% NH3*H2O: acetonitrile = 1: 1) to give the target product 068d (350 mg, yield 90.34%) as a light yellow solid.

[0752] LCMS: (ESI, m / z): 300.1 [M+H] +

[0753] Step 4: Synthesis of compound 068e (2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2- hydroxy-1-(1-methyl-1H-pyrazol-4-yl)propan-1-one)

[0754] To a solution of compound 068d (300 mg, 1.00 mmol) in acetic acid (10 mL) was added potassium thiocyanate (486 mg, 5.00 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction was cooled to 0 °C and a solution of bromine (176 mg, 1.00 mmol) in acetic acid (2 mL) was added dropwise. The reaction was stirred at room temperature for 12 h under nitrogen atmosphere. The reaction was concentrated under vacuum. The concentrate was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by C18 reverse phase (water 0.1% NH3*H2O: acetonitrile = 2:3) to give the target product 068e (220 mg, yield 61.59%) as a light yellow solid.

[0755] LCMS: (ESI, m / z): 357.0 [M+H] +

[0756] Fifth step Synthesis of compound 068 (1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2- hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-3-oxoprop-2-yl)benzo[d]thiazol-2-yl)urea)

[0757] To a solution of compound 068e (100 mg, 0.31 mmol) in N,N-dimethylformamide (3 mL) was added 1-fluoro-4-isocyanobenzene (47 mg, 0.34 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 2 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel normal phase column (petroleum ether: ethyl acetate = 1:1) to give the target product 068 (32 mg, yield 21.01%).

[0758] LCMS: (ESI, m / z): 494.1 [M+H] +

[0759] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.25 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.80 (s, 1H), 7.71 - 7.60 (m, 1H), 7.57 - 7.47 (m, 3H), 7.21 - 7.15 (m, 2H), 3.78 (s, 3H).

[0760] Step 6: Synthesis of compounds 068-A and 068-B

[0761] 068 (32 mg, 1.34 mmol) was separated by a chiral SFC under the following conditions (column specifications: 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: ethanol (+0.1% 7.0mol / L ammonia methanol solution); Flow rate: 120mL / min; Detection wavelength: UV 214nm; A:B = 55:45; Flow rate: 120mL / min; Column temperature: RT; Injection volume: 8mL; Cycle time: 3.2min; Solvent: ethanol (34mL), yielding crude product 068-A (14.50mg) and crude product 068-B (15.60mg). The crude 068-A was purified by high performance liquid chromatography (HPLC) under the following conditions: column specifications: Sunfire C18, 19*250mm, 10µm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20mL / min; elution gradient: 50% B, 16min; detection wavelength: 254nm / 220nm; retention time (min): 7.00-8.60), yielding the target compound 068-A (10.22mg, yield 31.94%). The crude 068-B was purified by high performance liquid chromatography (HPLC) under the following conditions: column specifications: Sunfire C18, 19*250mm, 10µm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20mL / min; elution gradient: 50% B for 16min; detection wavelength: 254nm / 220nm; retention time (min): 6.80-8.60), yielding the target compound 068-B (9.16mg, yield 28.63%).

[0762] 068-A:

[0763] LCMS:(ESI,m / z):494.0[M+H] + RT(min): 4.60-6.15

[0764] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.22(s,1H),8.31(s,1H),8.22(s,1H),8.18(s,1H),7.79( s,1H),7.75–7.60(m,1H),7.58–7.51(m,2H),7.51–7.44(m,1H),7.24–7.12(m,2H),3.77(s,3H).

[0765] 068-B:

[0766] LCMS: (ESI, m / z): 494.0 [M+H] + , RT (min): 7.12-9.19

[0767] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.26 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.79 (s, 1H), 7.69 - 7.61 (m, 1H), 7.58 - 7.51 (m, 2H), 7.51 - 7.46 (m, 1H), 7.22 - 7.13 (m, 2H), 3.77 (s, 3H).

[0768] Example 72

[0769] 1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-oxo-3-(1H-pyrazol-3-yl)propan-2- yl)benzo[d]thiazol-2-yl)urea 069

[0770] Using similar conditions as in example 71, the target compound 069 was prepared.

[0771] LCMS: (ESI, m / z): 480.2 [M+H] +

[0772] 1 H NMR (400 MHz, DMSO-d6) δ 14.04 - 13.35 (m, 1H), 10.90 (s, 1H), 9.19 (s, 1H), 8.57 - 7.98 (m, 2H), 7.76 - 7.42 (m, 5H), 7.17 (t, J = 8.8 Hz, 2H), 6.64 - 6.51 (m, 1H).

[0773] Example 73

[0774] 1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea 070

[0775] Using similar conditions as in example 71, the target compound 070 was prepared.

[0776] LCMS: (ESI, m / z): 494.2 [M+H] +

[0777] 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.29 (s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 7.74 - 7.60 (m, 2H), 7.58 - 7.50 (m, 2H), 7.46 - 7.43 (m, 1H), 7.20 - 7.13 (m, 2H), 6.52 (d, J = 2.4 Hz, 1H), 3.83 (s, 3H).

[0778] Example 74

[0779] 1 -(4-Fluorophenyl)-3-(6-(1,1,1 -trifluoro-2-hydroxy-3-(2-methyl-1 H-imidazol-5-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea 071

[0780] Using similar conditions in Example 71, the target compound 071 was prepared.

[0781] LCMS: (ESI, m / z): 494.0 [M+H] +

[0782] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.85 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.70 - 7.59 (m, 1H), 7.58 - 7.46 (m, 3H), 7.40 (s, 1H), 7.24 - 7.07 (m, 2H), 2.25 (s, 3H).

[0783] Example 75

[0784] 1 -(4-Fluorophenyl)-3-(6-(1,1,1 -trifluoro-2-hydroxy-3-(1 -methyl-1 H-imidazol-2-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea 072

[0785] Using similar conditions in Example 71, the target compound 072 was prepared.

[0786] LCMS: (ESI, m / z): 494.1 [M+H] +

[0787] 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 7.68 - 7.62 (m, 2H), 7.59 - 7.51 (m, 3H), 7.20 - 7.13 (m, 3H), 4.02 (s, 3H).

[0788] Example 76

[0789] 1 -(4-Fluorophenyl)-3-(6-(1,1,1 -trifluoro-2-hydroxy-3-(2-methylthiazol-5-yl)-3- oxopropan-2-yl)benzo[d]thiazol-2-yl)urea 073

[0790] Using similar conditions as in Example 71, the target compound 073 was prepared.

[0791] LCMS: (ESI, m / z): 511.0 [M+H] +

[0792] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.26 (s, 1H), 8.76 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.75 - 7.62 (m, 1H), 7.56 - 7.48 (m, 3H), 7.20 - 7.15 (m, 2H), 2.62 (s, 3H).

[0793] Example 77

[0794] N-(3-(Difluoromethylidene)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)thioureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 074

[0795] First Step Synthesis of compound 074a (2-(2-(bis[(tert-butoxy)carbonyl]amino)-1,3-benzothiazol-6-yl)-2-{[(tert-butoxy)carbonyl]oxy}-3,3,3-trifluoropropanoic acid ester)

[0796] Compound 001d (1.00 g, 3.12 mmol) was dissolved in dichloromethane (20 mL) at 0 degree Celsius, di-tert-butyl dicarbonate (3.40 g, 15.60 mmol) and 4-dimethylaminopyridine (0.19 g, 1.56 mmol) were added. The reaction was stirred at 50 degree Celsius for 3 hours. Water (50 mL) was added to dilute the reaction, which was extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to get the crude product, which was purified by silica gel normal phase chromatography column (petroleum ether: ethyl acetate = 10: 1) to get the target product 074a (1.40 g, yield 72.25%) as a light yellow solid.

[0797] LCMS: (ESI, m / z): 621.1 [M+H] +

[0798] Second step: Synthesis of compound 074b (2-(2-(tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid)

[0799] To the solution of compound 074a (1.40 g, 2.26 mmol) in methanol (40 mL), lithium hydroxide (0.54 g, 22.6 mmol) and water (10 mL) were added slowly, and the reaction was stirred at 50 degree Celsius for 2 hours. The reaction was concentrated under vacuum, the concentrate was diluted with water (50 mL), 1N hydrochloric acid aqueous solution was added slowly dropwise to adjust PH = 3-4, extracted with ethyl acetate (150 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to get the target product 074b (850 mg, yield 96.04%) as a light yellow solid crude product. Directly used in the next step.

[0800] LCMS: (ESI, m / z): 393.0 [M+H] +

[0801] Third step: Synthesis of compound 074c (tert-butyl (6-(3-((3-(difluoromethyl)cyclobutyl)amino)-1,1-difluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)carbamate)

[0802] To a solution of 074b (850 mg, 2.17 mmol) in N,N-dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (624 mg, 3.25 mmol) and 1-hydroxybenzotriazole (440 mg, 3.25 mmol) under nitrogen atmosphere. The reaction was stirred at room temperature for 15 min. To the reaction was added 3-(difluoromethyl)cyclobutane-1-amine hydrochloride (338 mg, 2.17 mmol) and N,N-diisopropylethylamine (842 mg, 6.51 mmol) under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give the target product 074c (620 mg, yield 58.00%) as a yellowish solid.

[0803] LCMS: (ESI, m / z): 494.0 [M+H] +

[0804] Fourth Step Synthesis of compound 074d (2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3- trifluoro-2-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)propan-1-one)

[0805] To a solution of compound 074c (100 mg, 0.20 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) dropwise at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was concentrated, the concentrate was diluted with 10 mL of water, quenched with 10% potassium carbonate aqueous solution (20 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was used directly in the next step.

[0806] LCMS: (ESI, m / z): 394.0 [M-56+H] +

[0807] Fifth Step Synthesis of compound 074

[0808] To 074d (70 mg, 0.18 mmol) in tert-butanol (3 mL), 1-fluoro-4-isothiocyanatobenzene (138 mg, 0.90 mmol), the reaction was stirred in a closed environment at 100 Celsius for 16 hours. To the reaction was added water (30 mL) to dilute, extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to get the crude product, the crude product was purified by high performance liquid, the conditions were as follows (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 64% B ~ 65% B, 16 min; detection wavelength: 254 nm / 220 nm), to get the target compound 074 (7.55 mg, yield 7.76%).

[0809] LCMS: (ESI, m / z): 547.0 [M+H] +

[0810] 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.65 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 - 7.69 (m, 2H), 7.68 - 7.59 (m, 1H), 7.57 - 7.44 (m, 1H), 7.31 - 7.02 (m, 2H), 4.40 - 4.31 (m, 1H), 2.98 - 2.79 (m, 3H), 2.78 - 2.69 (m, 1H).

[0811] Example 78

[0812] 2-(3-Chloro-2-(3-(4-fluorophenyl)ureido)benzo[d]thiophen-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide 075

[0813] (S)-2-(3-Chloro-2-(3-(4-fluorophenyl)ureido)benzo[d]thiophen-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide

[0814] (R)-2-(3-Chloro-2-(3-(4-fluorophenyl)ureido)benzo[d]thiophen-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide

[0815] First step Synthesis of compound 075b (1-(6-bromobenzo[b]thiophen-2-yl)-3-(4- fluorophenyl)urea)

[0816] To a solution of 6-bromo-l-benzothiophene-2-carboxylic acid (5 g, 19.45 mmol, 075a) in toluene (50 mL) was added triethylamine (3.94 g, 38.9 mmol) and diphenylphosphoryl azide (6.96 g, 25.29 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. 4-Fluoroaniline (2.59 g, 23.34 mmol) was added and the reaction was heated to 100 °C for 2 h. The reaction was cooled to room temperature and 100 mL of water was added. The solid was filtered and washed with ethyl acetate. The solid was dried under vacuum to give the target product 075b (2.2 g, 30.97% yield) as a white solid.

[0817] MS: (ESI, m / z): 366.9 [M+H] +

[0818] Second Step: Synthesis of compound 075c (l-(6-bromo-3-chlorobenzo[b]thiophen-2-yl)-3-(4-fluorophenyl)urea)

[0819] To a solution of 075b (2 g, 5.48 mmol) in N,N-dimethylformamide (20 mL) was added N-chlorosuccinimide (0.80 g, 6.03 mmol) at room temperature. The reaction was stirred at room temperature for 3 h. The reaction was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 3) and saturated brine once. The organic phase was dried over anhydrous sodium sulfate, concentrated and the crude product was purified by silica gel column chromatography (PE / EA = 30%) to give the target product 075c (1.6 g, 73.10% yield) as a yellow solid.

[0820] MS: (ESI, m / z): 398.9 [M+H] +

[0821] Third Step: Synthesis of compound 075d (ethyl 2-(3-chloro-2-(3-(4-fluorophenyl)ureido)benzo[b]thiophen-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[0822] To a solution of 075c (800 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.8 mL, 7 mmol) at room temperature. The reaction was stirred at -78 °C for 0.5 h. Ethyl 3,3,3-trifluoro-2-oxo propanoate (1190.63 mg, 7 mmol) was added and the reaction was stirred for 1 h. The reaction was quenched with 30 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30%) to give the target product 075d (400 mg, 40.71% yield) as a yellow solid.

[0823] MS: (ESI, m / z): 491.1 [M+H] +

[0824] Fourth Step Synthesis of compound 075 (2-(3-chloro-2-(3-(4-fluorophenyl)ureido)benzo[b]thiophen-6-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide)

[0825] 075d (100 mg, 0.20 mmol) was dissolved in 5 mL of ethylamine in ethanol at room temperature, and stirred at 80 °C for 16 hours. The reaction was concentrated, and the crude product was purified by Prep-HPLC (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 58% B ~ 58% B / 16 min; detection wavelength: 254 nm / 220 nm; retention time (min): 8.3-9.2) to give the target product 075 (11.31 mg, yield 11.33%).

[0826] MS: (ESI, m / z): 490.2 [M+H] +

[0827] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.49 (s, 1H), 8.23 (t, J = 5.9 Hz, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.73 - 7.68 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.20 - 7.13 (m, 2H), 3.16 - 3.09 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0828] Fifth Step Synthesis of compound 075-A / 075-B

[0829] Compound 075 (124 mg, 0.25 mmol) was separated by SFC with the following conditions (System: Waters SFC 150; column: Chromatography column specification: 250*30mm 10pm; mobile phase: A supercritical CO2, mobile phase B: isopropyl alcohol (+0.1% 7.0 mol / L amine methanol solution); A:B = 65:35; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 1.0 mL; cycle time: 5.31 min; solvents: methanol: distillation grade, supercritical CO2: food grade), retention time: 2.55-3.24 min, to obtain compound 075-A and purify by high performance liquid, conditions as follows (chromatography column specification: Waters 2767 / QDA Column: Pursuit XRs 10 C18 21.2*250mm*10pm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 56%-66% B, 18 min; detection wavelength: 254 nm / 214 nm) to obtain 075-A (10.11 mg, 2.89%).

[0830] The later peak, to obtain 075-B by high performance liquid purification, conditions as follows (chromatography column specification: Waters 2767 / QDA Column: Pursuit XRs 10 C18 21.2*250mm*10pm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 56%-66% B, 18 min; detection wavelength: 254 nm / 214 nm) to obtain 075-B (11.16 mg, 3.20%).

[0831] 075-A

[0832] MS: (ESI, m / z): 490.1 [M+H] + , RT (min): 2.55-3.24

[0833] 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.40 (s, 1H), 8.23 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.75 - 7.67 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.25 - 7.12 (m, 2H), 3.17 - 3.05 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0834] 075-B

[0835] MS: (ESI, m / z): 490.1 [M+H] +RT (min): 3.49-5.26

[0836] 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.47 (s, 1H), 8.23 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.75 - 7.67 (m, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.21 - 7.12 (m, 2H), 3.16 - 3.08 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H).

[0837] Example 79

[0838] N-(3-(Difluoromethylidene)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-(2-(3-(3- methylisothiazol-5-yl)ureido)benzo[d]thiazol-6-yl)propanamide 076

[0839] The target compound 076 was prepared using similar conditions described in Example 21.

[0840] LCMS: (ESI, m / z): 534.1 [M+H] +

[0841] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 6.66 (s, 1H), 4.39 - 4.32 (m, 1H), 2.99 - 2.82 (m, 4H), 2.28 (s, 3H).

[0842] Example 80

[0843] (R)-N-[3-(1,2-Difluorovinylidene)cyclobutyl]-2-hydroxy-3,3,3-trifluoro-2-{2-[3-(2- methylsulfophenothiazinyl)ureido]benzo[d]thiazol-6-yl}propanamide 077-A

[0844] The target compound 077-A was prepared using similar conditions described in Example 21.

[0845] LCMS: (ESI, m / z): 533.3 [M+H] +

[0846] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.40 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.70 - 7.63 (m, 2H), 7.01 (d, J = 5.4 Hz, 1H), 6.77 (d, J = 5.5 Hz, 1H), 4.39 - 4.32 (m, 1H), 2.96 - 2.82 (m, 3H), 2.72 (d, J = 10.3 Hz, 1H), 2.14 (s, 3H).

[0847] Example 81

[0848] (S)-N-[3-(1,2-difluoroethenyl)cyclobutyl]-2-hydroxy-3,3,3-trifluoro-2-{2-[3-(2- methylsulfanylphenothiazinyl)ureido]-benzo[d]thiazol-6-yl}propanamide 077-B

[0849] The target compound 077-B was prepared using similar conditions described in Example 21.

[0850] LCMS: (ESI, m / z): 533.3 [M+H] +

[0851] 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.40 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.70 - 7.63 (m, 2H), 7.01 (d, J = 5.4 Hz, 1H), 6.77 (d, J = 5.5 Hz, 1H), 4.39 - 4.32 (m, 1H), 2.96 - 2.82 (m, 3H), 2.72 (d, J = 10.3 Hz, 1H), 2.14 (s, 3H).

[0852] Example 82

[0853] 1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2-hydroxy-3-oxo-3-(pyridin-4-yl)propan-2- yl)benzo[d]thiazol-2-yl)urea 078

[0854] The target compound 078 was prepared using similar conditions described in Example 71.

[0855] LCMS: (ESI, m / z): 491.0 [M+H] +

[0856] 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.30 (s, 1H), 8.70 - 8.66 (m, 3H), 8.18 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.63 (dd, J = 4.5, 1.6 Hz, 2H), 7.54 (dd, J = 9.0, 4.9 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 8.9 Hz, 2H).

[0857] Example 83

[0858] 1-(6-(3-(3-cyanophenyl)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol- 2-yl)-3-(4-fluorophenyl)urea 079

[0859] The target compound 079 was prepared using similar conditions described in Example 71.

[0860] LCMS: (ESI, m / z): 515.1 [M+H] +

[0861] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.19 (s, 1H), 8.72 (s, 1H), 8.20 (s, 2H), 8.11 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.77 - 7.65 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.22 - 7.11 (m, 2H).

[0862] Example 84

[0863] N-(3-(difluoromethyl)cyclobutyl)-3,3-difluoro-2-(2-(3-(4-fluorophenyl)ureidophenyl)- 2-hydroxypropanamide 080

[0864] First Step Synthesis of compound 080b (ethyl 2-(4-bromophenyl)-3,3-difluoro-2- hydroxypropanoate)

[0865] To a solution of compound 2-(4-bromophenyl)-2-oxoethyl acetate (800 mg, 3.11 mmol, 080a) in tetrahydrofuran (10 mL) was added cesium fluoride (236.20 mg, 1.55 mmol) and (difluoromethyl)trimethylsilane (772.52 mg, 6.22 mmol) at room temperature. The reaction was stirred at room temperature for 12 h. The reaction was concentrated in vacuo. To the concentrate was added saturated aqueous sodium bicarbonate solution (50 mL) to quench, extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give the target product 080b (230 mg, yield 23.91%) as a yellow solid.

[0866] 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 8.9, 2.0 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.14 (s, 1H), 6.61 (t, J = 53.9 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 1.19 (dd, J = 8.9, 5.3 Hz, 3H).

[0867] Second Step Synthesis of compound 080c (2-(4-aminophenyl)-3,3-difluoro-2- hydroxypropanoic acid ethyl ester)

[0868] To a solution of compound 080b (230 mg, 0.74 mmol) in a mixture of ethanol (2 mL) and water (1 mL) was added N1,N2-dimethylcyclohexane-1,2-diamine (126.31 mg, 0.89 mmol), copper sulfate (118.11 mg, 0.74 mmol), sodium ascorbate (293.20 mg, 1.48 mmol) and sodium azide (144.32 mg, 2.22 mmol) at room temperature. The reaction was stirred at 80 °C for 3 h. To the reaction was added saturated aqueous sodium bicarbonate solution (20 mL) to quench, extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a black solid. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give the target product 080c (100 mg, yield 54.80%) as a yellow oil.

[0869] MS: (ESI, m / z): 297.0 [M+H] +

[0870] Step 3. Synthesis of compound 080d (ethyl 2-(2-aminobenzo[d]thiazol-6-yl)-3,3- difluoro-2-hydroxypropanoate)

[0871] To a solution of compound 080c (90 mg, 0.37 mmol) in acetic acid (1 mL) was added potassium thiocyanate (125.85 mg, 1.29 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction was cooled to 0 °C and bromine (65.04 mg, 0.41 mmol) in acetic acid (1 mL) was added dropwise. The reaction was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction was filtered and concentrated in vacuo to give 080d as brown oil. No purification was performed and the crude was used directly in the next step.

[0872] MS: (ESI, m / z): 303.0 [M+H] +

[0873] Step 4. Synthesis of compound 080e (ethyl 3,3-difluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoate)

[0874] At room temperature, 080d (100 mg, 0.33 mmol) was dissolved in N,N- dimethylformamide (2 mL) and 1-fluoro-4-isocyanatobenzene (0.075 mL, 0.66 mmol) was added slowly. The reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo and diluted with water (20 mL). The aqueous solution was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude. The crude was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the target product 080e (90 mg, yield 61.92%) as a white solid.

[0875] MS: (ESI, m / z): 440.1 [M+H] +

[0876] Step 5. Synthesis of compound 080f (3,3-difluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid)

[0877] To a solution of 080e (90 mg, 0.20 mmol) and lithium hydroxide (47.9 mg, 2 mmol) in methanol (2 mL) and water (1 mL) was added at room temperature. The reaction solution was stirred at 50 °C for 1 h. The reaction solution was concentrated, the pH value was adjusted to 4 with 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target product 080f (75 mg, yield: 89.02%) as a white solid.

[0878] MS: (ESI, m / z): 412.1 [M+H] +

[0879] Synthesis of compound 080

[0880] To a solution of 080f (90 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.26 mg, 0.33 mmol) and 1-hydroxybenzotriazole (44.59 mg, 0.33 mmol) at room temperature. After complete dissolution, 3-(difluoromethyl)cyclobutane-1-amine hydrochloride (51.33 mg, 0.33 mmol) was added, and finally N,N-diisopropylethylamine (85.30 mg, 0.66 mmol) was added. The reaction solution was stirred at room temperature for 1 h. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by reverse phase preparative chromatography (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 56% B; detection wavelength: 254 nm / 220 nm) to give the product 080 (31.74 mg, yield 27.56%).

[0881] MS: (ESI, m / z): 513.2 [M+H] +

[0882] 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.25 (s, 1H), 8.66 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.74 - 7.59 (m, 2H), 7.57 - 7.44 (m, 2H), 7.18 (t, J = 8.7 Hz, 2H), 7.09 (s, 1H), 6.77 (t, J = 54.1 Hz, 1H), 4.39 - 4.22 (m, 1H), 2.95 - 2.88 (m, 1H), 2.84 - 2.76 (m, 2H), 2.74 - 2.68 (m, 1H).

[0883] Example 85

[0884] 2-Amino-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanamide

[0885] (S)-2-Amino-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanamide

[0886] (R)-2-Amino-N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanamide

[0887] Synthesis of compound 081b (ethyl 2-azido-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanoate)

[0888] 001f (500 mg, 1.09 mmol) was added into tetrahydrofuran (8 mL), toluene (8 mL) was added, then diphenyl phosphorazide (599.94 mg, 2.18 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (331.88 mg, 2.18 mmol) were added, the reaction was stirred at 50 degree overnight. The reaction was concentrated to get the crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-0:1) to get the target compound 081b (350 mg, yield 66.37%) as a white solid.

[0889] MS: (ESI, m / z): 483.0 [M+H] +

[0890] Step 2. Synthesis of compound 081c (ethyl 2-amino-3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanoate)

[0891] 081b (300 mg, 0.62 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and Raney nickel (36.39 mg, 0.62 mmol) was added. The reaction was stirred at 50 °C for 1 h. The reaction was filtered through celite, and washed with ethyl acetate (30 mL). The filtrate was concentrated to give the crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0-0:1) to give the target compound 081c (200 mg, yield 70.46%) as a white solid.

[0892] MS: (ESI, m / z): 457.0 [M+H] +

[0893] Step 3. Synthesis of compound 081d (2-amino-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanoic acid)

[0894] 081c (180 mg, 0.39 mmol) was dissolved in water (5 mL) and methanol (10 mL) at room temperature, and lithium hydroxide (93.41 mg, 3.90 mmol) was added. The reaction was stirred at 50 °C for 1 h. The reaction was concentrated, and the pH was adjusted to 4 with 1 N hydrochloric acid solution. The reaction was extracted with ethyl acetate (60 mL x 3), and the organic phase was combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound 081d (153 mg, yield 90.57%) as a white solid.

[0895] MS: (ESI, m / z): 429.0 [M+H] +

[0896] Step 4. Synthesis of compound 081 (2-amino-N-(3-(difluoromethyl)cyclobutyl)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)propanamide)

[0897] 081d (150 mg, 0.35 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134.18 mg, 0.70 mmol) and 1-hydroxybenzotriazole (94.58 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (8 mL) at room temperature. The reaction solution was stirred at room temperature for 10 minutes, and 3-(difluoromethyl)cyclobutylamine hydrochloride (81.67 mg, 0.52 mmol) and N,N-diisopropylethylamine (226.17 mg, 1.75 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, which was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by high performance liquid chromatography under the following conditions (column specifications: Waters 2767 / QDA Column: Sunfire C18 19*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 58%~63% B; detection wavelength: 254 nm / 214 nm) to give the target compound 081 (76.78 mg, 41.41%).

[0898] MS: (ESI, m / z): 530.1 [M+H] +

[0899] 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.35 (s, 1H), 8.44 (d, J = 7.4 Hz, 1H), 8.17 (s, 1H), 7.69 - 7.51 (m, 4H), 7.25 - 7.09 (m, 2H), 4.39 - 4.26 (m, 1H), 3.23 (s, 2H), 2.97 - 2.86 (m, 2H), 2.82 - 2.74 (m, 1H), 2.63 - 2.57 (m, 1H).

[0900] Fifth Step Synthesis of compound 081-A / 081-B

[0901] Compound 081 (74.78 mg, 0.14 mmol) was separated by SFC under the following conditions (System: Waters SFC 150; Column: Chiralpak IC 250*30mm*5μm; Mobile phase A: 0.1% NH3-H2O, Mobile phase B: 0.1% NH3-CH3CN; Flow rate: 60 mL / min; Detection wavelength: 254 nm / 220 nm). Chromatography column specification: 250*30 mm 10 pm; mobile phase: A supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L amine methanol solution); A:B = 50:50; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 3.0 mL; cycle time: 9.8 min; solvents: methanol: distillation grade, supercritical CO2: food grade) to obtain compound 081-A (22.47 mg, 12.12%) and compound 081-B (26.15 mg, 14.10%).

[0902] 081-A

[0903] MS: (ESI, m / z): 530.2 [M+H] + , RT (min): 4.01-6.92

[0904] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.25 (s, 1H), 8.45 (d, J = 7.4 Hz, 1H), 8.17 (s, 1H), 7.65 - 7.49 (m, 4H), 7.22 - 7.13 (m, 2H), 4.38 - 4.27 (m, 1H), 3.23 (s, 2H), 2.99 - 2.87 (m, 2H), 2.81 - 2.73 (m, 1H), 2.64 - 2.58 (m, 1H).

[0905] 081-B

[0906] MS: (ESI, m / z): 530.1 [M+H] + , RT (min): 8.0-12.45

[0907] 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.47 (s, 1H), 8.44 (d, J = 7.4 Hz, 1H), 8.16 (s, 1H), 7.65 - 7.51 (m, 4H), 7.22 - 7.12 (m, 2H), 4.40 - 4.27 (m, 1H), 3.23 (s, 2H), 2.97 - 2.85 (m, 2H), 2.80 - 2.73 (m, 1H), 2.62 - 2.58 (m, 1H).

[0908] Example 86

[0909] N-(3-(difluoromethylidene)cyclobutyl)-2-(2-(3-(3,5-dimethylthiophen-2-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide 082

[0910] Using similar conditions of example 21, the target compound 082 was prepared.

[0911] LCMS: (ESI, m / z): 513.2 [M+H] +

[0912] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.22 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.69 - 7.62 (m, 2H), 6.45 (s, 1H), 4.39 - 4.32 (m, 1H), 2.97 - 2.82 (m, 3H), 2.72 - 2.66 (m, 1H), 2.33 (d, J = 0.8 Hz, 3H), 2.05 (s, 3H).

[0913] Example 87

[0914] N-(3-(difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(5-fluoro-3-methylthiophen-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 083

[0915] Using similar conditions of example 21, the target compound 083 was prepared.

[0916] LCMS: (ESI, m / z): 551.3 [M+H] +

[0917] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.34 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.72 - 7.62 (m, 2H), 6.43 (d, J = 2.5 Hz, 1H), 4.40 - 4.31 (m, 1H), 2.97 - 2.81 (m, 3H), 2.73 - 2.67 (m, 1H), 2.07 (s, 3H).

[0918] Example 88

[0919] (2S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(3-(methoxyimino)cyclobutyl)propanamide 084

[0920] Using similar conditions of Example 15, the target compound 084 was prepared.

[0921] MS: (ESI, m / z): 526.1 [M+H] +

[0922] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.22 (s, 1H), 8.74 (d, J = 7.4 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.77 - 7.61 (m, 2H), 7.59 - 7.45 (m, 2H), 7.27 - 7.11 (m, 2H), 4.37 - 4.22 (m, 1H), 3.69 (d, J = 3.1 Hz, 3H), 3.17 - 3.02 (m, 2H), 2.99 - 2.89 (m, 1H), 2.87 - 2.77 (m, 1H).

[0923] Example 89

[0924] (2S)-3,3,3-trifluoro-N-(3-(1-fluoroethylidene)cyclobutyl)-2-(2-((4-fluorophenyl)carbamoyl)amino)-1,3-benzothiazol-6-yl)-2-hydroxypropanamide 085

[0925] Using similar conditions of Example 15, the target compound 085 was prepared.

[0926] MS: (ESI, m / z): 527.3 [M+H] +

[0927] 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.31 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.65 (s, 2H), 7.58 - 7.51 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.37 - 4.10 (m, 1H), 2.95 - 2.78 (m, 2H), 2.77 - 2.59 (m, 2H), 1.80 - 1.70 (m, 3H).

[0928] Example 90

[0929] N-(3-(difluoromethylidene)cyclobutyl)-1-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)cyclobutane-1-carboxamide 086

[0930] First Step: Synthesis of compound 086b (1-(4-nitrophenyl)cyclobutane-1-carboxylic acid ethyl ester)

[0931] Ethyl 4-nitrophenylacetate (5.0 g, 23.90 mmol, 086a) was dissolved in N,N- dimethylformamide (60 mL) at 0 °C, sodium hydride (2.01 g, 50.19 mmol) was added, the reaction was stirred at room temperature for 15 min, cooled to 0 °C, 1,3- diiodopropane (14.14 g, 47.8 mmol) was added, stirred at 0 °C for 0.5 h, stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (3 x 200 mL), the combined organic phase was washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, concentrated, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give the target product 086b (3.3 g, yield 55.39%) as a yellow solid.

[0932] MS: (ESI, m / z): 250.1 [M+H] +

[0933] Second Step: Synthesis of compound 086c (1-(4-aminophenyl)cyclobutane-1-carboxylic acid ethyl ester)

[0934] 086b (2.0 g, 8.02 mmol) was dissolved in water (5 mL) and ethanol (20 mL) at room temperature, iron powder (1.34 g, 24.06 mmol) and ammonium chloride (4.29 g, 80.20 mmol) were added, the reaction was stirred at reflux for 2 h. The reaction was filtered, concentrated, extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the target crude product 086c (1.4 g, yield 79.57%) as a yellow solid, which was used directly in the next step.

[0935] MS: (ESI, m / z): 220.2 [M-H] -

[0936] Third Step: Synthesis of compound 086d (1-(2-aminobenzo[d]thiazol-6-yl)cyclobutane-1-carboxylic acid ethyl ester)

[0937] At room temperature, 086c (500 mg, 2.28 mmol) was dissolved in acetic acid (10 mL), potassium thiocyanate (775.50 mg, 7.98 mmol) was added, the reaction was stirred at room temperature for 1 hour, then bromine (400.80 mg, 2.51 mmol) was dissolved in acetic acid (2 mL) and slowly added to the reaction, the reaction was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction was filtered and concentrated to obtain the crude product 086d (450 mg, yield 71.41%) as a yellow solid, which was not purified and directly subjected to the next step.

[0938] MS: (ESI, m / z): 277.1 [M+H] +

[0939] Fourth step Synthesis of compound 086e (1-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)cyclobutane-1-carboxylic acid ethyl ester)

[0940] At room temperature, 086d (400 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (10 mL), 1-fluoro-4-isocyanobenzene (397.62 mg, 2.9 mmol) was slowly added, and the reaction was stirred at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL x 3) were added to the reaction, the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was then purified by normal phase (petroleum ether / ethyl acetate = 2 / 1) to obtain the target compound 086e (400 mg, yield 66.84%) as a white solid.

[0941] 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.24 (s, 1H), 7.84 (s, 1H), 7.68 - 7.44 (m, 3H), 7.26 (dd, J = 8.4, 1.8 Hz, 1H), 7.17 (t, J = 8.9 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.75 (m, 2H), 2.53 (s, 1H), 2.47 (d, J = 9.4 Hz, 1H), 2.00 - 1.78 (m, 2H), 1.10 (t, J = 7.1 Hz, 3H).

[0942] Fifth step Synthesis of compound 086f (1-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)cyclobutane-1-carboxylic acid)

[0943] 086e (200 mg, 0.48 mmol) was dissolved in a mixture solvent of methanol (4 mL), tetrahydrofuran (4 mL) and water (1 mL), sodium hydroxide (96 mg, 2.4 mmol) was added, the mixture was warmed to 50 °C and stirred for 4 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, the pH of the mixture was adjusted to 4-5 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product 086f (120 mg, yield 64.37%) as a white solid. Without purification, the next step was carried out directly.

[0944] MS: (ESI, m / z): 386.0 [M+H] +

[0945] Sixth step Synthesis of compound 086

[0946] 086f (0.12 g, 0.31 mmol) was dissolved in N,N-dimethylformamide (2 mL), 3- (difluoromethylidene) cyclobutane-1-amine (0.044 g, 0.37 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.089 g, 0.46 mmol), 1- hydroxybenzotriazole (0.063 g, 0.46 mmol) and N,N-diisopropylethylamine (0.080 g, 0.62 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by reverse phase preparative chromatography (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 63%~68% B; detection wavelength: 254 nm / 220 nm) to give the product 086 (25.31 mg, yield 16.71%).

[0947] MS: (ESI, m / z): 487.1 [M+H] +

[0948] 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.53 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 1.5 Hz, 1H), 7.63 - 7.48 (m, 3H), 7.30 (dd, J = 8.4, 1.8 Hz, 1H), 7.17 (t, J = 8.9 Hz, 2H), 4.33 - 4.17 (m, 1H), 2.93 - 2.81 (m, 2H), 2.77 - 2.67 (m, 2H), 2.63 - 2.54 (m, 2H), 2.46 - 2.35 (m, 2H), 1.86 - 1.67 (m, 2H).

[0949] Example 91

[0950] (S)-N-((1s,3R)-3-(2,2-difluorovinyl)cyclobutyl)-3,3,3-trifluoro-2-hydroxy-2-[2-(3-(4- fluorophenyl)ureido)-benzo[d]thiazol-6-yl]propanamide 087

[0951] The target compound 087 was prepared using similar conditions described in Example 15.

[0952] MS: (ESI, m / z): 545.1 [M+H] +

[0953] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.31 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.73 - 7.59 (m, 2H), 7.58 - 7.48 (m, 2H), 7.22 - 7.13 (m, 2H), 4.59 - 4.44 (m, 1H), 4.22 - 4.08 (m, 1H), 2.69 - 2.58 (m, 1H), 2.45 - 2.28 (m, 2H), 2.04 - 1.81 (m, 2H).

[0954] Example 92

[0955] (S)-N-((1r,3S)-3-(2,2-difluorovinyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 088

[0956] The target compound 088 was prepared using similar conditions described in Reference Example 15.

[0957] MS: (ESI, m / z): 545.2 [M+H] +

[0958] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.21 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.76 - 7.59 (m, 2H), 7.59 - 7.49 (m, 2H), 7.22 - 7.13 (m, 2H), 4.96 - 4.78 (m, 1H), 4.43 - 4.32 (m, 1H), 2.96 - 2.86 (m, 1H), 2.42 - 2.22 (m, 2H), 2.13 - 1.96 (m, 2H).

[0959] Example 93

[0960] 1-(6-(3-(1,2-dimethyl-1H-imidazol-4-yl)-1,1-difluoro-2-hydroxy-3-oxopropan-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea089

[0961] The title compound was prepared under the similar conditions described in Reference Example 71.

[0962] LCMS: (ESI, m / z): 508.1 [M+H] +

[0963] 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.43 (s, 1H), 8.68 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.57 - 7.51 (m, 3H), 7.17 (t, J = 8.9 Hz, 2H), 3.54 (s, 3H), 2.25 (s, 3H).

[0964] Example 94

[0965] 2-(2-(3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide (Compound 125)

[0966] First Step Synthesis of Compound 125b (2-(2,6-dibromophenyl)ethan-1-ol)

[0967] To a solution of 2-(2,6-dibromophenyl)acetic acid (002a, 5 g, 17.01 mmol) in tetrahydrofuran (50 mL) was added borane dimethyl sulfide (25.5 mL, 25.52 mmol) and reacted at room temperature for 2 h. After the reaction was completed, methanol was added to quench the reaction and concentrated to obtain a crude product, which was purified by normal phase (petroleum ether: ethyl acetate = 5:1) to obtain a white solid 125b (4.6 g, yield 96.59%).

[0968] MS: (ESI, m / z): 284.2 [M+H] +

[0969] Second Step Synthesis of compound 125c (1,3-dibromo-2-(2-bromomethyl)benzene)

[0970] To a solution of 125b (3.21 g, 11.47 mmol) in dichloromethane (50 mL) was added 1-bromopyrrolidine-2,5-dione (2.25 g, 12.62 mmol) and triphenylphosphine (4.51 g, 17.21 mmol) and reacted at room temperature for 3 h. After the reaction was completed, saturated aqueous ammonium chloride solution was slowly added to quench the reaction, dichloromethane (50 mL X 3) was added to extract, the organic phase was washed with saturated brine (50 mL X 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by normal phase (petroleum ether: ethyl acetate = 100:1) to obtain a colorless oil 125c (3.17 g, yield 80.64%).

[0971] 1 H NMR (400 MHz, DMSO-d6) d 7.67 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 8.0 Hz, 1H), 3.61 - 3.54 (m, 2H), 3.50 - 3.42 (m, 2H).

[0972] Third Step Synthesis of compound 125d (2-bromobicyclo[4.2.0]octa-1(6),2,4- triene)

[0973] To a solution of compound 125c (650 mg, 2.54 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (0.35 mL, 4.92 mmol) at -78 °C and reacted at -78 °C for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution (200 mL) was added to quench the reaction, ethyl acetate (50 mL X 3) was added to extract, the organic phase was washed with saturated brine (50 mL X 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by normal phase (petroleum ether: ethyl acetate = 100:1) to obtain a colorless oil 125d (1.44 g, yield 101.01%).

[0974] GCMS: (ESI, m / z): 182 [M]

[0975] Fourth Step Synthesis of compound 125e (N-(Bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-1,1-diphenylmethanimine)

[0976] To a solution of 125d (900 mg, 4.92 mmol) in toluene (10 mL) was added diphenylmethanimine (1.34 g, 7.38 mmol), Pd2(dba)3(451 mg, 0.49 mmol), BINAP (613 mg, 0.98 mmol) and sodium tert-butoxide (946 mg, 9.84 mmol) and stirred at 100 °C for 3 h under nitrogen protection. After the reaction was completed, water (200 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL X 3), the organic phase was washed with saturated brine (50 mL X 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by normal phase (petroleum ether: ethyl acetate = 5: 1) to give yellow oil 125e (460 mg, yield 33.02%).

[0977] MS: (ESI, m / z): 284.4 [M+H] +

[0978] Fifth Step Synthesis of compound 125f (Bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine)

[0979] 125e (460 mg, 1.62 mmol) was dissolved in a solution of hydrogen chloride dioxane (5 mL) and water (0.025 mL), and stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated to give yellow oil 125f (170 mg, yield 87.88%).

[0980] MS: (ESI, m / z): 320.2 [M+H] +

[0981] Sixth Step Synthesis of compound 125g (Ethyl 2-(2-(3-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[0982] To a solution of compound 125f (150 mg, 1.26 mmol) in dichloromethane (5 mL) was added triphosgene (187 mg, 0.63 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.78 mmol) at 0 °C and the reaction was allowed to proceed at room temperature for 1 h. Upon completion of the reaction, the reaction was concentrated to get yellow oil, which was dissolved in tetrahydrofuran (5 mL) and 2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid ethyl ester (404 mg, 1.26 mmol, synthesis method as per WO 2024155601 A1) was added and the reaction was allowed to proceed at room temperature for 1 h. Upon completion of the reaction, the reaction was concentrated to get crude, which was purified by normal phase (petroleum ether: ethyl acetate = 1:1) to get yellow solid 125g (310 mg, yield 52.91%).

[0983] MS: (ESI, m / z): 466.3 [M+H] +

[0984] Seventh step synthesis of compound 125

[0985] Compound 125g (300 mg, 0.64 mmol) was dissolved in ethylamine in ethanol (10 mL) and the reaction was allowed to proceed at 80 °C for 12 h. Upon completion of the reaction, the reaction was concentrated to get crude, which was purified by reverse phase preparative chromatography (conditions as follows: column specification: prep-HPLC (Waters 2767 / QDA), Column: SunFire C18, 19*250mm, 10um; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; flow rate: 20 ml / min; elution gradient: 52% B) to get the title compound 125 (5.7 mg, yield 1.90%).

[0986] MS: (ESI, m / z): 465.1 [M+H] + , RT (min): 8.4-9.5

[0987] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (brs, 1H), 9.34 (s, 1H), 8.22 (t, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.78 (brs, 1H), 7.69 - 7.63 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.1 Hz, 1H), 3.24 - 3.20 (m, 2H), 3.16 - 3.10 (m, 2H), 3.09 - 3.04 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0988] Example 95

[0989] N-ethyl-3,3,3-trifluoro-2-(2-(3-(5-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-2- yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (Compound 126)

[0990] (S)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(5-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-2- yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0991] (R)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(5-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-2- yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide

[0992] First Step Synthesis of Compound 126b (2-bromo-5-fluorobicyclo[4.2.0]octa-1(6),2,4- triene)

[0993] To a solution of 2,5-dibromobicyclo[4.2.0]octane-1(6),2,4-triene (126a, 1.12 g, 4.28 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.88 mL, 4.71 mmol) at -78 °C, after stirring for 1 h, N-(tert-butyl)-N-fluoro-2-methylpropane-2-sulfonamide (990 mg, 4.71 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (30 mL*3) was added to extract the organic phase, and the organic phase was washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by normal phase (petroleum ether: ethyl acetate = 100:1) to give colorless oil 126b (860 mg, yield 100%).

[0994] Second Step Synthesis of Compound 126c (N-(5-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-2- yl)-1,1-diphenylmethanamine)

[0995] To a solution of 126b (860 mg, 4.28 mmol) in toluene (10 mL) was added diphenylmethanimine (1.16 g, 6.42 mmol), Pd2(dba)3(392 mg, 0.43 mmol), BINAP (533 mg, 0.86 mmol) and sodium tert-butoxide (823 mg, 8.56 mmol) and reacted at 100 °C for 3 h under nitrogen protection. After the reaction was completed, water (200 mL) and ethyl acetate (50 mL*3) were added to the reaction solution, and the organic phase was washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then purified by normal phase (petroleum ether: ethyl acetate = 5: 1) to obtain yellow oil 126c (1.2 g, yield 93.10%).

[0996] MS: (ESI, m / z): 302.1 [M+H] +

[0997] Step 3 Synthesis of compound 126d (5-fluorobicyclo[4.2.0]octa-l(6),2,4-trien-2-amine)

[0998] 126c (600 mg, 1.99 mmol) was dissolved in a solution of hydrogen chloride dioxane (5 mL) and water (0.025 mL) and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated to obtain yellow oil 126d (100 mg, yield 36.62%).

[0999] MS: (ESI, m / z): 179.2 [M+H+41] +

[1000] Step 4 Synthesis of compound 126e (ethyl 3,3,3-trifluoro-2-(2-(3-(5-fluorobicyclo[4.2.0]octa-l(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoate)

[1001] To a solution of compound 126d (80 mg, 0.58 mmol) in dichloromethane (2 mL) was added triphosgene (172 mg, 0.58 mmol) and N, N-diisopropylethylamine (0.29 mL, 1.74 mmol) at 0 °C and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to get yellow oil, which was dissolved in tetrahydrofuran (3 mL) and added with compound 2-(2- aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid ethyl ester (149 mg, 0.46 mmol) and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was concentrated to get crude, which was purified by normal phase (petroleum ether: ethyl acetate = 1: 1) to get yellow solid 126e (180 mg, yield 63.83%).

[1002] MS: (ESI, m / z): 485.0 [M+H] +

[1003] Fifth step Synthesis of compound 126 (N-ethyl-3,3,3-trifluoro-2-(2-(3-(5- fluorobicyclo[4.2.0]octa-l(6),2,4-trien-2-yl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanamide)

[1004] Compound 126e (80 mg, 0.17 mmol) was dissolved in ethylamine in ethanol (8 mL) and stirred at 80 °C for 12 h. Upon completion of the reaction, the reaction mixture was concentrated to get crude, which was purified by reverse phase preparative chromatography (conditions as follows: column specification: Prep-HPLC (Waters 2767 / QDA), Column: SunFire C18, 19*250 mm, 10 um; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 52% B; to get compound 126 (19 mg, yield 23.80%).

[1005] MS: (ESI, m / z): 483.2 [M+H] +

[1006] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.18 (s, 1H), 8.22 (t, J = 5.8 Hz, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.72 - 7.60 (m, 2H), 7.38 - 7.32 (m, 1H), 6.96 (t, J = 7.7 Hz, 1H), 3.25 - 3.21 (m, 2H), 3.16 - 3.09 (m, 4H), 0.99 (t, J = 7.2 Hz, 3H).

[1007] Sixth step Synthesis of compound 126-A and 126-B

[1008] Compound 126 was purified by SFC with the following conditions (Waters SFC 150; column Column specification: 250*30mm 10pm; mobile phase: A supercritical CO2, mobile phase B: ethanol (+0.1% 7.0 mol / L amine methanol solution); A:B=50:50; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 8 mL; cycle time: 7.0 min; solvent: EtOH:distilled level, supercritical CO2:food grade), to obtain 126-A (3.5 mg, yield 18.42%) and 126-B (2.7 mg, yield 14.21%).

[1009] 126-A: MS: (ESI, m / z): 483.2 [M+H] + , RT (min): 1.8-2,4

[1010] 1 H NMR (400 MHz, DMSO-d6) d 10.89 (s, 1H), 9.18 (s, 1H), 8.22 (t, J = 5.8 Hz, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.72 - 7.60 (m, 2H), 7.38 - 7.32 (m, 1H), 6.96 (t, J = 7.7 Hz, 1H), 3.25 - 3.21 (m, 2H), 3.16 - 3.09 (m, 4H), 0.99 (t, J = 7.2 Hz, 3H).

[1011] 126-B: MS: (ESI, m / z): 483.2 [M+H] + , RT (min): 3.7-4.2

[1012] 1 H NMR (400 MHz, DMSO-d6) d 10.89 (s, 1H), 9.18 (s, 1H), 8.22 (t, J = 5.8 Hz, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.72 - 7.60 (m, 2H), 7.38 - 7.32 (m, 1H), 6.96 (t, J = 7.7 Hz, 1H), 3.25 - 3.21 (m, 2H), 3.16 - 3.09 (m, 4H), 0.99 (t, J = 7.2 Hz, 3H).

[1013] Example 96

[1014] N-ethyl-3,3,3-trifluoro-2-(2-(3-(7-fluoro-2,3-dihydro-1h-inden-4-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (compound 127)

[1015] First Step Synthesis of Compound 127b (N-(7-fluoro-2,3-dihydro-1h-inden-4-yl)-1,1-diphenylmethanamine)

[1016] To 127a (2.70 g, 12.55 mmol) in toluene (30 mL) was added, under nitrogen atmosphere, benzophenone imine (3.41 g, 18.83 mmol), tris(dibenzylideneacetone)dipalladium (1.15 g, 1.26 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (1.56 g, 2.51 mmol) and sodium tert-butoxide (2.41 g, 25.10 mmol) successively. The reaction was stirred at 90 °C under nitrogen atmosphere for 12 h. The reaction was cooled to room temperature. Water (100 mL) was added to the reaction to dilute, and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel normal phase column chromatography (petroleum ether: ethyl acetate = 2:1) to give the target product 127b (500 mg, yield 12.63%) as a yellowish oil.

[1017] LCMS: (ESI, m / z): 316.1 [M+H] +

[1018] Second Step Synthesis of Compound 127c (7-fluoro-2,3-dihydro-1h-inden-4-amine)

[1019] To 127b (500 mg, 12.55 mmol) in 1,4-dioxane (5 mL) was added, under nitrogen atmosphere, water (0.5 mL), hydrochloric acid in 1,4-dioxane (4 N, 10.00 mL, 40.00 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under vacuum. Water (30 mL) was added to the concentrate to dilute, and saturated sodium bicarbonate aqueous solution (50 mL) was added to quench. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by C18 reverse phase (water 0.1% NH3*H2O: acetonitrile = 1:1) to give the target product 127c (150 mg, yield 62.58%) as a yellowish solid.

[1020] LCMS: (ESI, m / z): 152.1 [M+H]+

[1021] Step 3. Synthesis of compound 127d (4-fluoro-7-isocyanate-2,3-dihydro-1H-indene)

[1022] To 127c (150 mg, 0.99 mmol) in tetrahydrofuran (3 mL) was added triethylamine (300 mg, 1.97 mmol) dropwise at 0 °C under nitrogen atmosphere and stirred for 10 minutes. To the above mixture in tetrahydrofuran (5 mL) was added dicitrtrate carbonate (587 mg, 1.98 mmol) dropwise at 0 °C under nitrogen atmosphere and the reaction was stirred at room temperature for 1 hour. TLC indicated the disappearance of starting material and the formation of a new spot. The reaction was concentrated in vacuo, co-evaporated with toluene (5 mL x 3) and concentrated to give the target product 127d (170 mg, yield 96.70%) as a light yellow solid. It was used directly in the next step.

[1023] Step 4. Synthesis of compound 127e (3,3,3-trifluoro-2-(2-(3-(7-fluoro-2,3-dihydro-1H- inden-4-yl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoic acid ethyl ester)

[1024] To 127d (200 mg, 0.62 mmol) in tetrahydrofuran (3 mL) was added triethylamine (291 mg, 2.88 mmol) dropwise at 0 °C under nitrogen atmosphere and stirred for 10 minutes. To the above mixture in tetrahydrofuran (5 mL) was added 2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoic acid ethyl ester (170 mg, 0.96 mmol) dropwise at 0 °C under nitrogen atmosphere and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel normal phase column chromatography (petroleum ether: ethyl acetate = 1: 1) to give the target product 127e (240 mg, purity 71%, yield 35.70%) as a light yellow solid.

[1025] Step 5. Synthesis of compound 127

[1026] To 127e (200 mg, 0.40 mmol) in ethanol (3 mL), add ethylamine in ethanol (30%, 5 mL, 26.95 mmol), stir the reaction at 80 degree Celsius in a closed vessel for 12 hours. Bring the reaction to room temperature and concentrate under vacuum to get the crude. Purify the crude by high performance liquid chromatography with the following conditions (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 56%-60% B, 16 min; detection wavelength: 254 nm / 220 nm) to get the target compound 127 (56.96 mg, yield 28.54%).

[1027] LCMS: (ESI, m / z): 497.2 [M+H] +

[1028] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.88 (s, 1H), 8.22 (t, J = 5.9 Hz, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.73 - 7.64 (m, 3H), 6.97 (t, J = 8.7 Hz, 1H), 3.17 - 3.09 (m, 2H), 2.95 - 2.86 (m, 4H), 2.16 - 2.07 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H).

[1029] Example 97

[1030] 2-(2-(3-(Dicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ureido)benzo[d]thiazol-6-yl)-N- ethyl-3,3,3-trifluoro-2-hydroxypropanamide (Compound 128)

[1031] First Step Synthesis of Compound 128b (N-(Dicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1,1- diphenylmethanimine)

[1032] To a solution of 128a (1000 mg, 3.82 mmol) in toluene (10 mL) was added diphenylmethanimine (690 mg, 3.82 mmol), Pd2(dba)3(349.81 mg, 0.38 mmol,), 2,2'-BINAP (475.72 mg, 0.76 mmol) and sodium tert-butoxide (730 mg, 7.64 mmol) and reacted at 100 °C under nitrogen protection. To the reaction solution was added water (50 mL) for dilution, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target product 128b (700 mg, yield: 50.62%) as a yellow solid.

[1033] MS: (ESI, m / z): 361.6 [M+H] +

[1034] Second step Synthesis of compound 128c (Bicyclo[4.2.0]octa-1(6),2,4-triene-3-amine)

[1035] To a solution of compound 128b (600 mg, 1.66 mmol) and ammonium formate (1.05 g, 16.60 mmol) in methanol (10 mL) was added palladium on carbon (60 mg, Purity 10%), and reacted at room temperature for 16 hours under nitrogen atmosphere. Filtration and concentration, to the reaction solution was added water (30 mL) and extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was further purified by normal phase (petroleum ether: ethyl acetate = 6:1) to give compound 128c (140 mg, yield: 70.94%) as a yellow oil.

[1036] MS: (ESI, m / z): 120.2 [M+H] +

[1037] Third step Synthesis of compound 128d (Ethyl 2-(2-(3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[1038] To a solution of compound 128c (300 mg, 2.52 mmol) in dichloromethane (3 mL) was added compound 128b (748 mg, 2.52 mmol) at 0 °C, stirred for 30 min, then N,N- diisopropylethylamine (977 mg, 7.56 mmol) was added, the reaction was carried out at room temperature for half an hour, the reaction solution was rotary evaporated, then tetrahydrofuran (3 mL) was added, followed by 2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2- hydroxypropanoic acid ethyl ester (404 mg, 1.26 mmol) and N,N-diisopropylethylamine (977 mg, 7.56 mmol), the reaction was carried out at room temperature overnight. Water (50 mL) was added to dilute the reaction solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the target compound 128d (200 mg, yield 17.07%) as a yellow oil.

[1039] MS: (ESI, m / z): 466.2 [M+H] +

[1040] Fourth step Synthesis of compound 128

[1041] To 128d (100 mg, 0.21 mmol) was added ethylamine in ethanol (5 mL) and the reaction was carried out at 80 °C overnight. The reaction solution was rotary evaporated, and the crude product was purified by high performance liquid chromatography under the following conditions (column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 53%-58% B, 17 min; detection wavelength: 254 nm / 220 nm) to give the target compound 128 (15 mg, yield 15.03%).

[1042] MS: (ESI, m / z): 465.3 [M+H] +

[1043] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.10 (s, 1H), 8.21 (t, J = 5.9 Hz, 1H), 8.16 (s, 1H), 7.77 (s, 1H), 7.66 (s, 2H), 7.34 (s, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 3.13 (d, J = 7.2 Hz, 2H), 3.10 (d, J = 3.3 Hz, 4H), 0.99 (t, J = 7.2 Hz, 3H).

[1044] Example 98

[1045] 2-(4-(difluoromethoxy)-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N- ethyl-3,3,3-trifluoro-2-hydroxypropanamide 129

[1046] (S)-2-(4-(difluoromethoxy)-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N- ethyl-3,3,3-trifluoro-2-hydroxypropanamide

[1047] (R)-2-(4-(difluoromethoxy)-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N- ethyl-3,3,3-trifluoro-2-hydroxypropanamide

[1048] First Step: Synthesis of compound 129b (ethyl 2-(4-amino-3-(difluoromethoxy)phenyl)- 3,3,3-trifluoro-2-hydroxypropanoate)

[1049] To a solution of 2-(difluoromethoxy)aniline (129a, 4 g, 25.14 mmol) and ethyl 3,3,3- trifluoro-2-oxopropanoate (4.70 g, 27.65 mmol) in toluene (90 mL) was added copper triflate (450 mg, 1.26 mmol) and the mixture was stirred at 60 °C for 16 h. Diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 0% ~ 30%) to give the target compound 129b (2 g, yield: 24.17%) as a light yellow oil.

[1050] LCMS: (ESI, m / z): 330.0 [M+H] +

[1051] Second Step: Synthesis of compound 129c (ethyl 2-(2-amino-4-(difluoromethoxy)-1,3- benzothiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[1052] To a solution of 129b (2 g, 6.07 mmol) and potassium thiocyanate (2.95 g, 30.35 mmol) in acetic acid (20 mL) was added liquid bromine (1.94 g, 12.14 mmol) at 0 °C, the mixture was stirred at room temperature for 16 hours. Added potassium carbonate aqueous solution to adjust pH = 8, diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with sodium thiosulfate aqueous solution, combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% ~ 40%) to give the target compound 129c (700 mg, yield: 29.83%) as a light yellow oil.

[1053] LCMS: (ESI, m / z): 387.1 [M+H] +

[1054] Step 3 Synthesis of compound 129d (ethyl 2-(4-(difluoromethoxy)-2-{[(4- fluorophenyl)carbamoyl]amino}-1,3-benzothiazol-6-yl)-3,3,3-trifluoro-2- hydroxypropanoate)

[1055] To a solution of 129c (650 mg, 1.68 mmol) in dichloromethane (7 mL) was added 1-fluoro-4-isocyanatobenzene (345.52 mg, 2.52 mmol), the mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% ~ 60%) to give the target compound 129d (530 mg, yield: 60.18%) as a light yellow oil.

[1056] LCMS: (ESI, m / z): 524.5 [M+H] +

[1057] Step 4 Synthesis of compound 129 (2-(4-(difluoromethoxy)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide)

[1058] To compound 129d (490 mg, 0.94 mmol) was added ethylamine (42.38 mg, 0.94 mmol) in ethanol (5 mL), the mixture was stirred at 70 °C for 16 h. Concentration gave 129 crude product, which was purified by high performance liquid, conditions as follows (column specification: Waters 2767 / QDA Column: Pursuit XRs 10 C18 21.2*250mm*10 pm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 60% B; detection wavelength: 254 nm / 220 nm), to give the target compound 129.

[1059] Fifth step Synthesis of compound 129-A and 129-B

[1060] Compound 129 was separated by SFC, conditions as follows (System: Waters SFC 150; column: column specification: 250*30mm 10 pm; mobile phase: A supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L amine ethanol solution); A:B = 80:20; wavelength: 214 nm; flow rate: 120 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 1.0 mL; cycle time: 4.3 min; solvent: EtOH: distilled grade, supercritical CO2: food grade), to give the target compound 129-A (20.46 mg, yield: 3.46%), to give the target compound 129-B (23.44 mg, yield: 4.54%).

[1061] 129-A:

[1062] MS: (ESI, m / z): 523.2 [M+H] + , RT (min): 2.4-3.35

[1063] 1 H NMR (400 MHz, DMSO-d6) d 11.44 (s, 1H), 9.29 - 9.12 (m, 1H), 8.28 (t, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.60 - 7.33 (m, 4H), 7.20 - 7.15 (m, 2H), 3.16 - 3.09 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[1064] 129-B:

[1065] MS: (ESI, m / z): 523.3 [M+H] +RT (min): 3.5-6.2

[1066] 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.08 (s, 1H), 8.29 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.57 - 7.32 (m, 4H), 7.21 - 7.17 (m, 2H), 3.16 - 3.10 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[1067] Example 99

[1068] N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-(prop-1-yn-1-yl)benzo[d]thiazol-6-yl)-2-hydroxypropanamide 130

[1069] First Step: Synthesis of compound 130b (ethyl 2-(4-amino-3-bromophenyl)-3,3,3-trifluoro-2-hydroxypropanoate)

[1070] At room temperature, 130a (1.945 g, 7.39 mmol) was added into N,N-dimethylformamide (30 mL), N-bromosuccinimide (1.32 g, 7.39 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added into the reaction solution, and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 ~ 0:100) to give the target compound 130b (1.957 g, yield 77.41%) as a yellow oil.

[1071] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.6, 1.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.59 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[1072] Second Step: Synthesis of compound 130c (ethyl 2-(2-amino-4-bromobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[1073] To a solution of 130b (1.849 g, 5.40 mmol) in acetic acid (30 mL) was added potassium thiocyanate (1.84 g, 18.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Then bromine (0.95 g, 5.94 mmol) was dissolved in acetic acid (3 mL) and added slowly to the above reaction mixture. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, washed with ethyl acetate (50 mL), and the filtrate was concentrated. The pH value of the solution was adjusted to 8 with sodium bicarbonate aqueous solution, and the solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 to 50:100) to give the target compound 130c (1.20 g, 55.62% yield) as a yellow solid.

[1074] MS: (ESI, m / z): 400.9 [M+H] +

[1075] Step 3. Synthesis of compound 130d (ethyl 2-(4-bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[1076] To a solution of 130c (300 mg, 0.75 mmol) in N,N-dimethylformamide (8 mL) was added p-fluorophenyl isocyanate (133.68 mg, 0.98 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by reverse phase (0.1% formic acid / acetonitrile) column to give the target compound 130d (400 mg, 99.24% yield) as a light yellow solid.

[1077] MS: (ESI, m / z): 538.0 [M+H] +

[1078] Step 4. Synthesis of compound 131 (2-(4-bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide)

[1079] To a solution of 130d (200 mg, 0.37 mmol) in ethanol (8 mL) was added ethylamine at room temperature. The reaction mixture was stirred at 70 °C overnight. The reaction mixture was concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 to 50:50) to give the target compound 131 (155 mg, 77.64% yield) as a white solid.

[1080] MS: (ESI, m / z): 537.0 [M+H] +

[1081] Fifth Step Synthesis of compound 130

[1082] Compound 131 was dissolved in tetrahydrofuran (2 mL) with 131 (100 mg, 0.19 mmol), cuprous iodide (7.24 mg, 0.038 mmol) dichlorobis(triphenylphosphine)palladium (1.33 mg, 0.0019 mmol), triethylamine (96.13 mg, 0.95 mmol) and propargyl N,N-dimethylformamide solution (0.95 mL, 0.95 mmol) at room temperature, replaced with nitrogen for three times, the reaction solution was stirred at 70 °C for 25 hours. The reaction solution was quenched by adding water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by normal phase column (petroleum ether: ethyl acetate = 100:0 ~ 0:100), preparative plate (petroleum ether: ethyl acetate = 1:2) and high performance liquid, conditions as follows (column specifications: Waters 2767 / QDA Column: Pursuit XRs 10 C18 21.2*250mm*10μm; mobile phase A: water (0.03% ammonia water), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 49%-54% B; detection wavelength: 254 nm / 214 nm), to give the target compound 130 (1.13 mg, yield 1.22%).

[1083] MS: (ESI, m / z): 495.2 [M+H] + , RT (min): 6.80-7.30

[1084] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.19 (t, J = 5.9 Hz, 1H), 7.89 (s, 1H), 7.75 - 7.65 (m, 1H), 7.65 - 7.54 (m, 2H), 7.53 (s, 1H), 7.08 (t, J = 8.8 Hz, 2H), 3.16 - 3.11 (m, 2H), 2.10 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H). Example 100

[1085] 2-(4-bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide 131

[1086] (S)-2-(4-bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide

[1087] (R)-2-(4-bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide

[1088] First step synthesis of compounds 131-A and 131-B

[1089] Compound 131 (150 mg, 0.28 mmol) was separated by SFC with the following conditions (System: Waters SFC 150; Column: Column specification: 250*30mm 10pm; mobile phase: A supercritical CO2, mobile phase B: ethanol (+0.1% 7.0 mol / L amine ethanol solution); A:B = 70:30; wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; back pressure: 100 bar; injection volume: 0.5 mL; cycle time: 5.0 min; solvent: EtOH: distilled grade, supercritical CO2: food grade), to give compound 131-A (59.07 mg, 39.38%) and 131-B (51.86 mg, 34.57%).

[1090] 131-A

[1091] MS: (ESI, m / z): 537.0 [M+H] + , RT (min): 3.4-4.2

[1092] 1 H NMR (400 MHz, DMSO-d6) d 11.48 (s, 1H), 9.03 (s, 1H), 8.30 (t, J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.55 - 7.51 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 3.16 - 3.09 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[1093] 131-B

[1094] MS: (ESI, m / z): 537.0 [M+H] + , RT (min): 4.5-6.8

[1095] 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.05 (s, 1H), 8.30 (t, J = 5.9 Hz, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.55 - 7.50 (m, 2H), 7.19 (t, J = 8.9 Hz, 2H), 3.16 - 3.08 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[1096] Example 101

[1097] (Z)-1-(4-Fluorophenyl)-3-(12-hydroxy-11-keto-12-(trifluoromethyl)-2-oxo-10-aza- 1(4,6)-benzo[d]thiazolacyclododecan-4-en-12-yl)urea 132

[1098] First Step: Synthesis of compound 132b (tert-butyl (4-bromo-2-hydroxyphenyl) carbonate)

[1099] Compound 132b (tert-butyl (4-bromo-2-hydroxyphenyl) carbonate) was synthesized by dissolving 2-amino-5-bromophenol (10 g, 53.19 mmol, 132a) in tetrahydrofuran (50 mL), slowly adding di-tert-butyl dicarbonate (11.61 g, 53.19 mmol) in tetrahydrofuran (10 mL) dropwise, stirring the system at room temperature for 16 hours, and concentrating to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% ~ 20%) to obtain the target compound 132b (10.2 g, yield 66.5%) as a white solid.

[1100] MS: (ESI, m / z): 228.9 [M+H] +

[1101] Second Step: Synthesis of compound 132c (tert-butyl (2-(allyloxy)-4-bromophenyl) carbamate)

[1102] Compound 132b (4.8 g, 16.66 mmol) was dissolved in acetonitrile (50 mL), and a reaction solution of cesium carbonate (16.28 g, 49.98 mmol) and allyl bromide (2.22 g, 18.33 mmol) was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution to dilute, and extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target product 132c (4.8 g, yield 87.79%) as a yellow oil.

[1103] MS: (ESI, m / z): 272.0 [M-56+H] +

[1104] Step 3. Synthesis of compound 132d (ethyl 2-(3-(allyloxy)-4-((tert- butoxycarbonyl)amino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoate) To a solution of compound 132c (4.7 g, 14.32 mmol) in anhydrous tetrahydrofuran (50 mL) was added n-butyllithium (20 mL, 2.5 M) at -78 °C and stirred for 30 min, then 3,3,3-trifluoroacetone acid ethyl ester (10.96 g, 64.44 mmol) was added and stirred for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution (20 mL) to quench the reaction, then water (100 mL) was added to dilute, extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by reverse phase to give the target product 132d (1.6 g, yield 26.64%) as yellow oil.

[1105] MS: (ESI, m / z): 364.1 [M-56+H] +

[1106] Step 4. Synthesis of compound 132e (2-(3-(allyloxy)-4-((tert- butoxycarbonyl)amino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid)

[1107] To a solution of compound 132d (1.55 g, 3.70 mmol) in methanol (10 mL) was added lithium hydroxide (0.44 g, 18.5 mmol) in water (2 mL) at 50 °C and reacted for 0.5 h. The reaction mixture was concentrated, ethyl acetate (50 mL) was added, then water (40 mL) was added, followed by 1 M hydrochloric acid (10 mL) to adjust the pH to 2-3, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, which was purified by silica gel chromatography column (ethyl acetate 100%) to give the target product 132e (450 mg, yield 31.11%) as white solid.

[1108] Step 5. Synthesis of compound 132f ((2-(allyloxy)-4-(1,1,1-trifluoro-3-(hex-5- en-1-ylamino)-2-hydroxy-3-oxopropan-2-yl)phenyl)carbamic acid tert-butyl ester)

[1109] Compound 132e (300 mg, 0.77 mmol), hex-5-ene-1-amine (84.00 mg, 0.85 mmol), EDCI (221.41 mg, 1.16 mmol) and HOBT (156.06 mg, 1.16 mmol) were added into DMF (3 mL) at room temperature, then DIEA (298.54 mg, 2.31 mmol) was added into the reaction solution, and the mixture was reacted at room temperature for 1 h. Water (30 mL) was added for dilution, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 40%) to obtain the target compound 132f (220 mg, yield: 60.74%) in the form of yellow oil.

[1110] MS: (ESI, m / z): 417.2 [M-56+H] +

[1111] Step 6 Synthesis of compound 132g (tert-butyl (12-hydroxy-11-oxo-12- (trifluoromethyl)-2-oxa-10-aza-1(1,3)-benzocyclododec-4-en-16-yl)carbamate)

[1112] Compound 132f (100 mg, 0.21 mmol) was dissolved in DCM (2 mL) at room temperature, and then benzylidenebis(tricyclohexylphosphine)dichlororuthenium (17.58 mg, 0.021 mmol) was added into the reaction solution, and the mixture was reacted at 50°C for 16 h. The reaction solution was filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0% to 40%) to obtain the target compound 132g (50 mg, yield: 53.16%) in the form of oil.

[1113] MS: (ESI, m / z): 389.2 [M-56+H] +

[1114] Step 7 Synthesis of compound 132h (16-amino-12-hydroxy-12-(trifluoromethyl)- 2-oxa-10-aza-1(1,3)-benzocyclododec-4-en-11-one)

[1115] Compound 132g (40 mg, 0.090 mmol) was dissolved in DCM (2 mL) at room temperature, and then trifluoroacetic acid (1 mL) was added into the reaction solution, and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated to obtain a crude product 132h (40 mg), which was used directly in the next step without purification.

[1116] MS: (ESI, m / z): 327.2 [M-17+H] +

[1117] Eighth Step Synthesis of compound 132i ((Z)-l-(4-fluorophenyl)-3-(12-hydroxy- 11-keto-12-(trifluoromethyl)-2-oxa-10-aza-l(4,6)-benzo[d]thiazacyclododec-4- en-12-yl)urea)

[1118] To a solution of compound 132h (30 mg, 0.087 mmol) in acetic acid (1 mL) was added potassium thiocyanate (29.59 mg, 0.30 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction was cooled to 0 °C and bromine (15.29 mg, 0.096 mmol) in acetic acid (1 mL) was added dropwise. The reaction was stirred at room temperature for 12 h under nitrogen atmosphere. The reaction was filtered and the filtrate was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude 132i as a black solid.

[1119] MS: (ESI, m / z): 402.1 [M+H] +

[1120] Ninth Step Synthesis of compound 132 ((Z)-l-(4-fluorophenyl)-3-(12-hydroxy- 11-keto-12-(trifluoromethyl)-2-oxa-10-aza-l(4,6)-benzo[d]thiazacyclododec-4- en-12-yl)urea)

[1121] To a solution of 132i (20 mg, 0.050 mmol) in DMF (2 mL) was added 1-fluoro-4- isocyanatobenzene (13.71 mg, 0.10 mmol) slowly. The reaction was stirred at room temperature for 2 h. The reaction was concentrated to give the crude product. The crude product was purified by reverse phase preparative chromatography (column size: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.03% ammonia), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 39%~50% B; detection wavelength: 254nm / 220nm) to give the product 132 (2.5 mg, 9.32% yield).

[1122] MS: (ESI, m / z): 539.2 [M+H] +

[1123] 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 7.79 (s, 1H), 7.61 (s, 1H), 7.56 - 7.52 (m, 2H), 7.16 (t, J = 8.9 Hz, 2H), 6.82 (s, 1H), 5.47 - 5.22 (m, 2H), 4.92 - 4.76 (m, 1H), 4.74 - 4.56 (m, 1H), 3.55 - 3.40 (m, 1H), 2.03 - 1.98 (m, 1H), 1.72 - 1.64 (m, 2H), 1.37 - 1.20 (m, 3H), 0.91 - 0.84 (m, 1H).

[1124] Example 102

[1125] N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2- hydroxypropanamide 133

[1126] (S)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2- hydroxypropanamide

[1127] (R)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2- hydroxypropanamide

[1128] First Step: Synthesis of compound 133b (tert-butyl (5-bromothiophen-2-yl)carbamate)

[1129] To a solution of compound 5-bromothiophene-2-carboxylic acid (10 g, 48.30 mmol, 133a) in tetrahydrofuran (100 mL) was added triethylamine (14.66 g, 144.90 mmol) and diphenyl phosphorazide (15.95 g, 57.96 mmol) dropwise at 0 degree Celsius under nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under vacuum, dissolved in tert-butanol (100 mL) and stirred at 90 degree Celsius under nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature and concentrated under vacuum to get the crude product. The crude product was concentrated and purified by silica gel normal phase column chromatography (petroleum ether: ethyl acetate = 4: 1) to get the target product 133b (12.6 g, yield 93.79%) as a grey solid.

[1130] Second Step: Synthesis of compound 133c (ethyl 2-(5-(tert-butoxycarbonyl)amino)thiophen-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate)

[1131] To a solution of compound 133b (12.60 g, 45.30 mmol) in tetrahydrofuran (120 mL) was added sodium hydride (4.53 g, 60%, 113.25 mmol) at 0 °C and stirred for 0.5 h. The reaction was cooled to -78 °C and n-butyllithium tetrahydrofuran solution (27.54 mL, 68.86 mmol) was added dropwise. The reaction was stirred at -78 °C for 0.5 h. 3,3,3-trifluoro-2-oxo-propionic acid ethyl ester (11.56 g, 67.95 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred at -78 °C for 0.5 h and then allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give the target product 133c (6.00 g, yield 35.86%) as a yellow oil.

[1132] LCMS: (ESI, m / z): 370.1 [M+H] +

[1133] Third Step Synthesis of compound 133d (tert-butyl (5-(3-(ethylamino)-1,1,1- trifluoro-2-hydroxy-3-oxopropan-2-yl)thiophen-2-yl)carbamate)

[1134] To a solution of compound 133c (6.00 g, 16.24 mmol) in ethanol (30 mL) was added ethylamine in ethanol (30%, 60 mL, 323.43 mmol) and stirred at 80 °C in a sealed vessel for 12 h. The reaction was allowed to cool to room temperature and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give the target product 133d (4.60 g, yield 76.87%) as a yellow solid.

[1135] LCMS: (ESI, m / z): 369.1 [M+H] +

[1136] Fourth Step Synthesis of compound 133e (2-(5-aminothiophen-2-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide)

[1137] To a solution of compound 133d (4.40 g, 11.95 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) slowly dropwise under 0 degree Celsius atmosphere. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated and azeotroped with dichloromethane (50 mL x 3) and concentrated to get the crude compound 133e (4.50 g, yield 98.55%) as a purple oil which was used directly for the next step.

[1138] LCMS: (ESI, m / z): 269.1 [M+H] +

[1139] Fifth Step Synthesis of compound 133f (N-((5-(3-(ethylamino)-1,1,1- trifluoro-2-hydroxy-3-oxopropan-2-yl)thiophen-2-yl)aminomethyl)benzamide)

[1140] To a solution of compound 133e (4.50 g, 11.77 mmol) in acetone (50 mL) was added benzoyl isothiocyanate (2.59 g, 15.89 mmol). The reaction was stirred at 65 degree Celsius under nitrogen atmosphere for 3 hours. The reaction was allowed to cool to room temperature and concentrated under vacuum to get the crude. The crude was concentrated and purified by silica gel normal phase column chromatography (petroleum ether: ethyl acetate = 4: 1) to get the target product 133f (2.80 g, yield 55.13%) as a light yellow solid.

[1141] LCMS: (ESI, m / z): 432.1 [M+H] +

[1142] Sixth Step Synthesis of compound 133g (N-ethyl-3,3,3-trifluoro-2-hydroxy-2-(5- thioureidothiophen-2-yl)propanamide)

[1143] To a solution of compound 133f (2.50 g, 5.79 mmol) in methanol (30 mL) was added potassium carbonate (2.40 g, 17.37 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was allowed to cool to room temperature and concentrated under vacuum to get the crude. The crude was concentrated and purified by silica gel normal phase column chromatography (dichloromethane: methanol = 10: 1) to get the target product 133g (1.30 g, yield 68.54%) as a light yellow solid.

[1144] LCMS: (ESI, m / z): 328.0 [M+H] +

[1145] Seventh Step Synthesis of compound 133h (compound 2-(2-aminothieno[2,3- d]thiazol-5-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide)

[1146] To a solution of compound 133g (1.00 g, 3.05 mmol) in acetic acid (12 mL) was added a solution of bromine (244 mg, 1.52 mmol) in acetic acid (3 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was concentrated under vacuum. To the concentrate was added saturated aqueous sodium bicarbonate solution (50 mL) to quench and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by C18 reverse phase (0.1% NH3H2O) to give the target product 133h (220 mg, yield 22.14%) as a light yellow oil.

[1147] LCMS: (ESI, m / z): 326.0 [M+H] +

[1148] Eighth Step Synthesis of compound 133 (N-ethyl-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanamide)

[1149] To a solution of compound 133h (200 mg, 0.61 mmol) in N,N-dimethylformamide (5 mL) was added 1-fluoro-phenyl isocyanate (92 mg, 0.67 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 2 h. To the reaction was added water (30 mL) to dilute and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by C18 reverse phase (0.1% NH3H2O) to give the target product 133 (55 mg, yield 19.35%).

[1150] LCMS: (ESI, m / z): 463.1 [M+H] +

[1151] 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.12 (s, 1H), 8.45 (t, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.55 - 7.48 (m, 3H), 7.20 - 7.15 (m, 2H), 3.20 - 3.12 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[1152] Ninth Step Synthesis of compound 133-A / 133-B

[1153] Compound 133 (53 mg, 0.12 mmol) was separated by chiral SFC with the following conditions (column specifications: 250*30 mm 10 pm; mobile phase A: supercritical CO2, mobile phase B: isopropyl alcohol (+0.1% 7.0 mol / L ammonia methanol solution); detection wavelength: UV 214 nm; A:B = 45:55; flow rate: 80 mL / min; column temperature: RT; injection volume: 3 mL; cycle time: 5.7 min; solvent: methanol (45 mL), to obtain target product 133-A (14.19 mg, yield 26.77%) and target product 133-B (16.12 mg, yield 30.42%).

[1154] 133-A:

[1155] LCMS: (ESI, m / z): 463.1 [M+H] + , RT (min): 2.80-4.15

[1156] 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.12 (s, 1H), 8.45 (t, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.55 - 7.47 (m, 3H), 7.22 - 7.12 (m, 2H), 3.20 - 3.11 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[1157] 133-B:

[1158] LCMS: (ESI, m / z): 463.1 [M+H] + , RT (min): 5.24-7.44

[1159] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.06 (s, 1H), 8.45 (t, J = 5.9 Hz, 1H), 8.16 (s, 1H), 7.57 - 7.44 (m, 3H), 7.25 - 7.12 (m, 2H), 3.21 - 3.11 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[1160] Example 103

[1161] (S)-N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanamide 134-A (S)-N-(3-(Difluoromethyl)cyclobutyl)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanamide 134-A

[1162] First Step: Synthesis of compound 134b (2-nitro-3-thiocyanothiophene)

[1163] To a solution of 3-bromo-2-nitrothiophene (7.63 g, 36.68 mmol, 134a) in dimethyl sulfoxide (80 mL) was added potassium thiocyanate (10.69 g, 110.04 mmol) and the reaction was stirred at 80 °C for 16 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-20%) to give the target compound 134b (6.83 g, yield: 90.0%) as a yellow oil. TLC was used to monitor the completion of the reaction.

[1164] Second Step: Synthesis of compound 134c (thieno[2,3-d]thiazol-2-amine)

[1165] To a solution of compound 134b (6.83 g, 36.68 mmol) in acetic acid (70 mL) was added iron powder (10.23 g, 183.17 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was adjusted to pH about 13 with potassium carbonate aqueous solution, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-70%) to give the target compound 134c (3.41 g, yield: 59.51%) as a yellow oil.

[1166] LCMS: (ESI, m / z): 156.8 [M+H] +

[1167] Third Step: Synthesis of compound 134d (5-bromothieno[2,3-d]thiazol-2-amine)

[1168] To a solution of compound 134c (3.41 g, 21.83 mmol) in acetic acid (40 mL) was added N-bromosuccinimide (3.89 g, 21.83 mmol) and the reaction was stirred at 80 °C for 1 h. The reaction was adjusted to pH about 13 with potassium carbonate aqueous solution, diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-70%) to give the target compound 134d (3 g, yield: 58.46%) as a yellow oil.

[1169] LCMS: (ESI, m / z): 234.8 [M+H] +

[1170] Fourth Step Synthesis of compound 134e (1-(5-bromothieno[2,3-d]thiazol-2-yl)-3-(4- fluorophenyl)urea)

[1171] To a solution of compound 134d (1.8 g, 7.66 mmol) in dichloromethane (20 mL) was added 1-fluoro-phenyl isocyanate (1.58 g, 11.49 mmol), the reaction was stirred at room temperature for 1 hour. The reaction was spin dried, the crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0~80%) to give the target compound 134e (1 g, yield: 35.09%) as a yellow oil.

[1172] LCMS: (ESI, m / z): 373.9 [M+H] +

[1173] Fifth Step Synthesis of compound 134f (3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanoic acid ethyl ester)

[1174] To a solution of compound 134e (500 mg, 1.34 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (134 mg, 3.35 mmol) at 0 °C, the reaction was stirred at 0 °C for 30 minutes, n-butyllithium (128.76 mg, 2.01 mmol) was added at -78 °C, the reaction was stirred at -78 °C for 30 minutes, 3,3,3-trifluoro-2-oxo propanoic acid ethyl ester (683.76 mg, 4.02 mmol) was added at -78 °C, the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with aqueous ammonium chloride solution, diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, spin dried, the crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0~70%) to give the target compound 134f (180 mg, yield: 28.92%) as a yellow oil.

[1175] LCMS: (ESI, m / z): 463.9 [M+H] +

[1176] Sixth Step Synthesis of compound 134f-A ((S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanoic acid ethyl ester)

[1177] Compound 134f (180 mg, 0.389 mmol) was separated by chiral SFC, the conditions were as follows (column specifications: 250*30mm*10um; mobile phase A: supercritical CO2, mobile phase B: methanol (+0.1% 7.0 mol / L ammonia methanol solution); flow rate: 140 mL / min; detection wavelength: UV 214 nm; A:B = 50:50; flow rate: 140 mL / min; column temperature: RT; injection volume: 6 mL; cycle time: 2.8 min; solvent: methanol (20 mL). Pre-peak retention time (min): 4.22-6.80, obtained 134f-A (80 mg, 0.173 mmol), post-peak retention time (min): 7.75-11.68, obtained 134f-B (80 mg, 0.173 mmol).

[1178] Seventh step Synthesis of compound 134g-A ((S)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanoic acid)

[1179] Compound 134f-A (78.78 mg, 0.17 mmol) was dissolved in ethanol (1 mL) and water (0.5 mL) at room temperature, sodium hydroxide (68 mg, 1.70 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was adjusted to pH about 3 with 1M dilute hydrochloric acid, extracted with ethyl acetate (10 mL X 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target product 134g-A (70 mg, yield 94.58%) as a white solid.

[1180] LCMS: (ESI, m / z): 436.0 [M+H] +

[1181] Eighth step Synthesis of compound 134-A ((S)-N-(3-(difluoromethyl)cyclobutyl)-3,3,3- trifluoro-2-(2-(3-(4-fluorophenyl)ureido)thieno[2,3-d]thiazol-5-yl)-2-hydroxypropanamide)

[1182] To a solution of 134g-A (69.66 mg, 0.16 mmol) and 3-(difluoromethyl)cyclobutane-1- amine (38.12 mg, 0.32 mmol) in N,N-dimethylformamide (1 mL) was added N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (61.34 mg, 0.32 mmol), 1- hydroxybenzotriazole (43.24 mg, 0.32 mmol) and ethyldiisopropylamine (144.75 mg, 1.12 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was purified by Prep-HPLC (column specification: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 mL / min; elution gradient: 65%-70% B, 16 min; detection wavelength: 254 nm / 220 nm) to give the target product 134-A (27.40 mg, yield 31.92%).

[1183] LCMS: (ESI, m / z): 537.2 [M+H] +

[1184] 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.10 (s, 1H), 8.95 (d, J = 7.7 Hz, 1H), 8.26 (s, 1H), 7.55 - 7.47 (m, 3H), 7.20 - 7.13 (m, 2H), 4.55 - 4.19 (m, 1H), 2.99 - 2.78 (m, 4H).

[1185] Biological evaluation

[1186] Test 1, the disclosed compound in the recombinant PTH1R overexpression cell line CHO- PTH1R for the activation of PTH1R.

[1187] The concentration of cAMP generated after treating the CHO-PTH1R cell line with the compound was detected by the HTRF method. cAMP is a key second messenger in GPCR signaling and can feedback the agonistic state of GPCR. The highest concentration of this test was 10000 nM, with a 3-fold dilution gradient, 10 concentrations, and duplicate hole detection.

[1188] 1.1 Experimental materials

[1189] 1.1.1 Reagents and consumables

[1190] Table A

[1191] 1.1.2 Instruments

[1192] Table B

[1193] 1.2 Experimental procedure

[1194] (1) Prepare 1X Stimulation buffer. Dilute the compound gradient 10 concentrations, which are 10 times of the concentration to be tested, with 1X Stimulation buffer.

[1195] (2) Uniformly spread the cells in the 384-well reaction plate, 200 cells per well, with a volume of 9 μL per well. Then add 1 μL of the compound solution diluted to 10X detection concentration in step b) to each well, and incubate in the cell incubator for 30 min.

[1196] (3) Add Eu-cAMP and ULight TM -anti-cAMP antibody to the reaction wells after dilution to the working concentration with detection buffer, and incubate at room temperature for 1 h after centrifugation.

[1197] 1.3 Experimental results

[1198] After the incubation is completed, the microplate reader detects the readings at 665 nm and 620 nm under excitation at 330 nm. The signal value of each well is Emission 665 nM / Emission 620 nM, and the reaction activation percentage of each compound well can be calculated according to the formula "single-hole activation rate = (average value of negative control signal-single-hole signal value) / (average value of negative control signal-average value of teriparatide 300 nM signal)*100%" The four-parameter Logistic regression model is used to fit the activation rate-concentration curve, and finally the EC 50 value of the compound is calculated. The results are shown in Table 1.

[1199] Table 1 Test results of the test compounds

[1200] Conclusion: The above data show that the representative compounds of the present application have good PTH1R agonistic activity.

[1201] Test Example 2: Pharmacokinetic study of the test compounds in SD rats

[1202] 2.1 Experimental method

[1203] 2.1.1 Experimental reagents

[1204] Compound 006, 014, 034, 036, 044, 048, 061, 084.

[1205] 2.1.2 Experimental animals

[1206] Healthy adult male Sprague-Dawley (SD) rats were used as experimental subjects in this study, and the body weight of the animals of this strain was controlled within the range of 250 ± 20 g. The animals were adaptively fed in a standardized laboratory environment for 7 days (temperature 22 ± 2°C, humidity 55 ± 10%, 12 h day-night cycle), and were free to eat sterilized feed and pure water.

[1207] 2.1.3 Drug preparation

[1208] An appropriate amount of sample was weighed, and a formulation of 5% DMSO + 10% Solutol + 85% saline was used to prepare 0.3 mg / mL.

[1209] 2.1.4 Experimental operation

[1210] Before the experiment, 8 groups of a total of 24 rats (3 rats per group) were randomly allocated to each drug administration group according to body weight, corresponding to test compounds 006, 014, 034, 036, 044, 048, 061, and 084, respectively. The experiment used a single gavage administration method, and all test compounds were administered at an equivalent dose of 2 mg / kg. The animals were fasted for 12 hours before administration (free water). Blood samples were collected at the following 9 time points using intravenous blood sampling method: before administration (0 h) as baseline, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Each time, about 0.3 mL of whole blood was collected through jugular vein puncture into a heparinized vacuum blood collection tube, immediately placed in an ice water bath, and centrifuged at 3000 x g for 10 minutes within 30 minutes to separate the plasma, which was then aliquoted into EP tubes and stored at -80°C for testing.

[1211] 2.2 Experimental results

[1212] The pharmacokinetic study of the compounds in SD rats in this application was determined by the above experiment, and the key pharmacokinetic parameters including peak time (T max ), peak concentration (C max ), half-life (t 1 / 2 ), and area under the curve (AUC 0-t ) were calculated. The results are shown in Table 2.

[1213] Table 2 Pharmacokinetic parameters of SD rats administered with compounds by gavage Note: ND indicates that the data was not detected.

[1214] The results show that in the single gavage administration of SD rats of the preferred compound 006 of the application, t 1 / 2 and AUC 0-t both show better results than other preferred compounds, and have better pharmacokinetic properties.

[1215] Test Example 3, Pharmacokinetic study of test compound in beagle dogs

[1216] 3.1 Experimental methods

[1217] 3.1.1 Experimental reagents

[1218] Compound 006, Control Compound A; wherein the structure of Control Compound A is The preparation method refers to WO2024155601A1.

[1219] 3.1.2 Experimental animals

[1220] Healthy adult male beagle dogs were selected as experimental model animals in this study, and the body weight of all dogs ranged from 10 to 12 kg.

[1221] 3.1.3 Drug preparation

[1222] An appropriate amount of sample was weighed and prepared into 0.3 mg / mL using a formulation of 5% DMSO + 10% Solutol + 85% Saline.

[1223] 3.1.4 Experimental operation

[1224] Before the experiment, the animals were adaptively fed in a SPF environment for 14 days (temperature 22±1℃, humidity 50±5%, 12h day-night cycle), and free access to standard dog food and sterilized drinking water. The experiment used a completely randomized grouping method, and 6 male beagle dogs were randomly divided into 2 groups (3 dogs in each group), and there was no statistically significant difference in body weight between groups (p>0.05). The animals in group A were given a single gavage of 2 mg / kg of compound 006, and the animals in group B were given a single gavage of 2 mg / kg of control compound A. Blood was collected intravenously before and at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration. The concentration of 006 and control compound A in beagle dog plasma was detected by using a verified LC-MS / MS method.

[1225] Pre-dose treatment: 12 hours of fasting before the experiment (free access to water), and water was removed 2 hours before administration.

[1226] Gavage operation: special soft-headed gavage needle for dogs was used for oral administration, and the stomach tube was flushed with 3mL of normal saline after administration. The animal behavior and physiological response were closely observed during the administration period.

[1227] Blood sampling time points: Blood samples were collected from the forelimb vein at pre-dose (0h baseline) and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h post-dose for a total of 9 time points. About 1mL of whole blood was collected each time into pre-chilled sodium heparin anticoagulant tubes, which were immediately placed in an ice bath. The plasma was separated by centrifugation at 3000xg for 15 minutes within 30 minutes after blood collection, aliquoted into cryotubes and stored at -80℃ ultra-low temperature freezer to avoid repeated freeze-thawing.

[1228] 3.2 Experimental results

[1229] The pharmacokinetic study of compound 006 and control compound A in beagle dogs in the present application was determined by the above experiment, and the peak time (T max ), peak concentration (C max ), half-life (t 1 / 2 ), and area under the curve (AUC 0-∞ ) were calculated. The results are shown in Table 3.

[1230] Table 3 Pharmacokinetic parameters of compound 006 and control compound A in beagle dogs administered 2mg / kg by gavage

[1231] The results show that in the pharmacokinetic study of compound 006 in beagle dogs after single gavage administration, t 1 / 2 and AUC 0-∞ are significantly better than those of control compound A, and it has better pharmacokinetic properties.

[1232] Test Example 4: Recovery effect of blood calcium and blood phosphorus of test compound in TPTx rats

[1233] 4.1 Purpose of the experiment

[1234] The purpose of this experiment is to explore the changes in blood calcium and blood phosphorus caused by the test substance in a TPTx male SD rat model after single oral gavage administration or continuous 7-day daily single oral gavage administration.

[1235] 4.2 Experimental scheme

[1236] 4.2.1 Preparation of drug preparation

[1237] Test drug: compound 006

[1238] Solvent: 10% DMSO + 10% Kolliphor EL + 80% (10% hydroxypropyl-b-cyclodextrin in 0.752% glycine buffer);

[1239] Preparation steps:

[1240] (1) First, an appropriate amount of compound was dissolved in DMSO, and ultrasonic was applied to obtain a uniform solution;

[1241] (2) An equal amount of Kolliphor EL solution was added to (1);

[1242] (3) Finally, eight equal amounts of 10% hydroxypropyl-b-cyclodextrin dissolved in 0.752% glycine solution were added to make up the volume and mix well.

[1243] 4.2.2 Information of Experimental Animals

[1244] Species: Rats

[1245] Strain: SD

[1246] Gender: Male

[1247] Body weight: 350-450g

[1248] Weeks of age: 8-9 weeks of age

[1249] Source: Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.

[1250] 4.2.3 Experimental Design

[1251] After normal male rats were subjected to TPTx or sham operation, they were divided into groups according to the postoperative D8 or D9 blood calcium value (blood calcium concentration <8mg / dL) and body weight balance, and 5 animals were allocated to each group. After completing the planned blood sample collection, the animals were euthanized by inhaling carbon dioxide. The information of animal single-dose grouping and sampling is shown in Table 4, and the information of animal continuous 7-day once-daily-dose grouping and sampling is shown in Table 5.

[1252] Table 4 Information of animal single-dose grouping and sampling

[1253] Table 5 Information of animal continuous 7-day once-daily-dose grouping and sampling

[1254] 4.2.4 Data Processing

[1255] The measurement data was expressed as mean ± standard deviation (Mean ± SD), and the graph was drawn using Graphpad 8.4.3.

[1256] 4.3 Experimental Results

[1257] 4.3.1 Single-dose results and analysis

[1258] The experiment evaluates the improvement of compound 006 on low blood calcium and high blood phosphorus in the TPTx model of rats in single administration. The effects of compound 006 on blood calcium and blood phosphorus in the TPTx model of rats in single administration are shown in Figures 1-2. There is a dose-effect relationship in the 15mpk and 30mpk groups of compound 006. After single administration, the blood calcium concentration of the animals in the two groups gradually increases compared with the vehicle group, and approaches the normal physiological level at 10h after administration. From 10h to 24h after administration, the blood calcium concentration of the animals in the compound 006 treatment group slowly increases in the physiological range and then remains stable to 48h, during which the blood calcium fluctuates in the normal range. The blood phosphorus concentration slowly decreases to the normal physiological level after administration, and the maintenance time is equivalent to the blood calcium concentration.

[1259] 4.3.2 Results analysis of continuous 7-day once-daily oral administration

[1260] The experiment evaluates the improvement of compound 006 on low blood calcium and high blood phosphorus in the TPTx model of rats during multiple administrations. The effects of compound 006 on blood calcium and blood phosphorus in the TPTx model of rats in the last administration of 7-day continuous administration are shown in Figures 3-4, and the effects of compound 006 on blood calcium and blood phosphorus in the TPTx model of rats in the 7-day continuous administration are shown in Figures 5-6. Compared with the rats in the vehicle group, the blood calcium concentration of the animals in each administration group of compound 006 gradually increases, and there is a significant dose-dependent effect. Before administration on the 4th day, the blood calcium concentration of the animals in the 10mpk and 15mpk administration groups of compound 006 is higher than that in the sham operation group, and the blood calcium concentration in the 5mpk administration group is close to the physiological range of rats. From the 4th day to the 7th day, the blood calcium concentration can be stably maintained through single administration. After administration on the 7th day, the blood calcium concentration of the animals in the three administration groups of compound 006 slightly increases, the blood calcium concentration in the 15mpk administration group of compound 006 is slightly higher than the Top value in the physiological range of blood calcium, and the blood calcium concentration in the 10mpk and 5mpk administration groups of compound 006 fluctuates in the normal physiological range. The improvement effect of compound 006 on high blood phosphorus is basically consistent with that on low blood calcium, but the maintenance time of the effect on blood phosphorus is longer than that on blood calcium.

[1261] The results show that the preferred compound 006 of the present application can effectively increase blood calcium and reduce blood phosphorus in the TPTx model of rats, and maintain blood calcium in the normal range, and supports the once-daily oral administration scheme.

[1262] The above has exemplarily described the embodiments of the technical scheme of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the protection scope of the claims of the present application.

Claims

A compound of formula (I), racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof; wherein, Z is selected from O or S; Q is selected from N or CR q ; R q is selected from H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano C 1-6 alkylene, halo C 1-6 alkyl or halo C 1-6 alkoxy; Ring D is selected from the group consisting of no substitution or optionally substituted with one, two, or more R d substituted phenyl ring, 5-6 membered heteroaromatic ring; each R d are the same or different, each independently selected from the group consisting of H, OH, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, or two adjacent R d together with the atoms to which each is respectively attached form a C 4-10 cycloalkenyl ring; Ring F is selected from wherein 1 and 2 are fused to the left heteroaromatic ring and 3 is fused to the right side is connected to; Y is selected from N or CR5; wherein R5is selected from H, CN, OH, halogen, unsubstituted or optionally substituted with one, two or more R c substituted C 1- 6alkyl, C 1-6 alkoxy, C 2-10 alkynyl or C 3-6 cycloalkyl; each R c are the same or different, independently from each other, selected from CN, OH, halogen or C 1-6 alkyl; or, R5is linked to R via L (-R5'-L-R'-) to form a macrocyclic compound, wherein R5' is selected from -O- or a direct bond; L is selected from C 3-20 alkylene or C 3-20 alkenylene; R' is selected from -NH-; R3is selected from haloC 1-6 alkyl; R4 is selected from OH or NH2; or R3, R4and the carbon atom to which they are both attached form C 3-6 cycloalkyl ring; R is selected from -NR1R2, C 1-6 alkoxy or unsubstituted or optionally substituted by one, two or more R r substituted by one, two or more R r are the same or different, independently of one another, selected from H, OH, CN, halogen or C 1-6 alkyl; R1and R2are the same or different, independently of one another, selected from the group consisting of H, unsubstituted or optionally substituted by one, two or more R a substituted by one, two or more R 1- 10 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a1 R a2 , C 1-10 alkyl, -R a3 - cycloalkyl; the cycloalkyl is selected from the group consisting of C 3-10 cycloalkyl, heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, S; each R a are the same or different, independently of one another, selected from the group consisting of C 1-10 alkyl, haloC 1-10 alkyl, haloC 1-10 alkyl, -R 1-10 alkyl-NH-, (C 1-10 alkyl)2-N-, -S(=O)(=NH)C 1-10 alkyl, = N-O-C 1-6 alkyl, cyano C 1-10 alkyl, -NHS(=O)2C 1-10 alkyl or C 2-10 alkynyl; R6, R7are identical or different and independently of each other selected from H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, -C(=O)R a4 ; R a1 and R a2 are identical or different and independently of each other selected from H, C 1-6 alkyl; R a3 is selected from C 1-6 alkylene; R a4 is selected from hydroxy or C 1-10 alkoxy; or R1and R2, together with the atoms to which they are attached, form an unsubstituted or optionally substituted 4-10 membered heterocyclyl ring; b substituted ring B selected from 4-10 membered heterocyclyl; each R b the same or different, each independently selected from OH, C 1-10 alkyl, haloC 1-10 alkyl, C 1-10 alkyl-NH-, (C 1-10 alkyl)2-N-, -NH-S(=0)2-C 1-10 alkyl, -S(=0)2-C 1-10 alkyl, (C 1-10 alkyl)2-N-C(=0)-, C 1-10 alkoxy-C(=0)-, cyanoC 1-10 alkyl, C 1-10 alkoxy, haloC 1-6 alkoxy, R6, R7are the same or different, independently of one another selected from the group consisting of H, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, hydroxy-C 1-6 alkyl, -C(=O)R a4 ; R a4 selected from the group consisting of hydroxy or C 1-10 alkoxy; R8is selected from H, CN or halogen; or, R8, R5, together with the carbon atoms to which each is respectively attached, collectively form C 4-8 carbocyclic or 4-8 membered heterocyclic ring. The compound according to claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that, Ring D is selected from the group consisting of no substitution or optionally substituted with one, two, or more R d substituted phenyl ring, a substituted thiophene ring (e.g. ), a thiazole ring (e.g. ), a pyridine ring, a pyrimidine ring (e.g. ), a pyrazole ring (e.g. )； Preferably, each R d are the same or different, independently of each other, selected from H, F, CI, Br, CN, methoxy, methyl or two adjacent R d together with the atoms to which they are each attached form a C 4-6 cycloalkenyl ring; Preferably, each R d are the same or different, independently of one another, selected from H, F, CI, Br, CN, methoxy or methyl; Preferably, each R d are the same or different, independently of each other, selected from H, F or two adjacent R d together with the atoms to which they are each attached form More preferably, Ring D is selected from The compound according to claim 1 or 2, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that, Q is selected from N or CR q ; R q is selected from H, OH, CN, halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano C 1-3 alkylene, halo C 1-3 alkyl or halo C 1-3 alkoxy; Preferably, R q is selected from H, CN, F, CI, Br, methyl, trifluoromethyl, cyanomethyl, 2,2,2-trifluoroethyl or -OF2CI; Y is selected from N or CR5, wherein R5is selected from H, CN, OH, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl; Preferably, R5 is selected from H, CN, OH, F, Cl, Br, methyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, cyclopropyl or 1-propynyl; or R5and R are linked through L (-R5'-L-R'-) to form a macrocycle, wherein R5' is selected from -O- and L is selected from C 3-20 alkylene; R' is selected from -NH-; preferably, L is selected from -CH2-CH=CH-(CH2)4-; R3is selected from fluoroC 1-3 alkyl; Preferably, R3 is selected from trifluoromethyl or difluoromethyl; Preferably, R4 is selected from OH or NH2; or R3, R4 and the carbon atom to which they are jointly attached form a cyclobutane ring. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-3, characterized in that, R is selected from -NR1R2, C 1-6 alkoxy or unsubstituted or optionally substituted by one, two or more R r substituted phenyl or 5-6 membered nitrogen containing heteroaryl; each R r are the same or different, independently of one another, selected from H, CN or C 1-6 alkyl; Preferably, the 5-6 membered nitrogen-containing heteroaryl is selected from phenyl, pyrazolyl, imidazolyl, thiazolyl or pyridyl; Preferably, said 5-6 membered nitrogen-containing heteroaryl is selected from phenyl, Preferably, each R r are the same or different, independently of one another, selected from H, CN or methyl; Preferably, said C 1-6 alkoxy is selected from C 1-3 alkoxy; R1and R2are the same or different, independently of one another, selected from the group consisting of H, unsubstituted or optionally substituted by one, two or more R a substituted by one, two or more R 1- 6alkyl, cycloalkyl, 3- to 6-membered heterocyclyl containing one N heteroatom; R a1 R a2 , C 1-6 alkoxy, -R a3 -cycloalkyl, 3- to 6-membered heterocyclyl containing one N heteroatom; R 3-6 cycloalkyl, 3- to 6-membered heterocyclyl containing one N heteroatom; R a1 , R a2 , R a3 having the definition as claimed in claim 1 ; or, R1and R2, together with the atoms to which they are attached, form an unsubstituted or optionally substituted 5- or 6-membered heteroaryl ring having one, two, or three ring heteroatoms selected from N, O, and S; b substituted ring B selected from 4-9 membered nitrogen-containing heterocyclyl; Preferably, R1and R2are the same or different and independently of one another selected from H, unsubstituted or optionally substituted with one, two or more R a substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R substituted with one, two or more R sub Preferably, ring A is selected from cyclobutyl, cyclopentyl, azetidinyl (e.g. )； Preferably, ring B is selected from Preferably, each R a Same or different, selected independently from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=O)(=NH)C 1-6 alkyl, cyano C 1-6 alkyl, -NHS(=0)2C 1-6 alkyl, = N-O-C 1-6 alkyl, haloC 1-6 alkoxy or C 2-6 alkynyl; Preferably, each R b They are either the same or different, and are independently selected from OH and C. 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, (C 1-6 alkyl)2-NC(=O)-, C 1-6 Alkoxy-C(=O)-, cyano C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy; R6, R7are the same or different and independently of one another selected from the group consisting of H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, -COOH, -C(=O)C 1-3 alkoxy; R6, R7are the same or different and independently of one another selected from the group consisting of H, halogen, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, -COOH; Preferably, R6, R7 are the same or different, independently of each other selected from H, F, Cl, Br, methyl, hydroxymethyl, trifluoromethyl, -COOH; Preferably, R6is selected from halogen or H, R7is selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, -COOH, -C(=O)C 1- 3alkoxy; R6is selected from halogen, R7is selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, -COOH; Preferably, selected from the group consisting of Preferably, each R a Same or different, selected independently from C 1-6 Alkylene, Halogenated C 1-6 Alkylene, hydroxyl-halogenated C 1-6 Alkylene, C 1- 6-alkyl-NH-, (C 1-6 alkyl)2-N-, -S(=O)(=NH)C 1-6 Alkyl, cyano C 1-6 Alkyl group, -NHS(=O)2C 1-6 Alkyl, HOOC-halogenated C 1-6 Alkylene = N-O-C 1-6 alkyl, haloC 2-6 alkenyl, haloC 1-6 alkoxy or C 2-6 alkynyl; Preferably, each R a identically or differently, independently of one another, are selected from the group consisting of methylamino, dimethylamino, ethynyl, 1-propynyl, difluoromethoxy or trifluoromethoxy; Preferably, each R b They are either the same or different, and are independently selected from OH and C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkylene, hydroxyl-halogenated C 1-6 Alkylene, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, (C 1-6 alkyl)2-NC(=O)-, C 1-6 Alkoxy-C(=O)-, cyano-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; Preferably, each R b identically or differently, independently of one another, are selected from OH, methyl, methylamino, dimethylamino, Preferably, R a1 and R a2 are the same or different, independently of each other, selected from H or C 1-3 alkyl; Preferably, R a1 and R a2 are the same or different, independently of each other, selected from H or ethyl; Preferably, R a3 selected from C 1-3 alkylene; Preferably, R a3 is selected from methylene. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-4, characterized in that, R is selected from ethoxy, R8, R5, together with the carbon atom to which each is attached, form C 4-8 a carbocyclic or 4-8 membered heterocyclic ring; provided that, at least one substituent in the radical wherein R6, R7 have the definitions described above; R8, R5, together with the carbon atom to which each is attached, form C 4-6 cycloalkenyl ring or 4-6 membered heterocyclic ring; Preferably, R8, R5, and the carbon atom to which they are each attached jointly form a 3-6 membered heterocyclyl containing one O heteroatom; Preferably, R8, R5, together with the carbon atom to which each is attached, form The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-5, characterized in that, The compound is selected from the following structures: wherein Z, ring D, Y, R, R1, R2, R3, R4, R8, R q independently of one another have the meanings as defined in any of claims 1 to 5; Preferably, the compound is selected from the following structures: wherein Z, ring D, ring F, Q, Y, R1, R3, R4, R6, R7, R8 independently of each other have the definitions as described in any one of claims 1-5; E is selected from C 1-6 alkylene; or E is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R a substituted ring A; or R1and E, together with the atoms to which they are attached, form an unsubstituted or optionally substituted b substituted ring B; said ring A, ring B, R a , R b independently of one another have the definitions indicated above; Preferably, E is selected from a cyclobutane ring, or R1 and E form a nitrogen-containing cyclobutane with the nitrogen atom to which they are attached; Preferably, the compound is selected from the following structures: wherein ring A, ring B, Y, R1, R8, R a , R b , R d each independently have the meaning as defined in any one of claims 1 to 5; m, n, p are the same or different, and are independently selected from 0, 1, 2, 3, 4 or 5; Preferably, the compound is selected from the following structures: wherein Z, ring D, ring F, Q, R3, R4, R6, R7 independently of each other have the definitions as described in any one of claims 1-5. The compound according to claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that, The compound is selected from the following structures: A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds, its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds of any one of claims 1-7. The use of at least one of the compounds, its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds of any one of claims 1-7, or the pharmaceutical composition of claim 8, for the manufacture of a medicament; Preferably, the use is the use for the manufacture of a medicament for PTH1R agonists; Preferably, the use is the use for the manufacture of a medicament for the treatment or prevention of hypoparathyroidism and / or osteoporosis; Preferably, the use is the use for the manufacture of a medicament for the treatment or prevention of osteoporosis, bone fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumor calcinosis.

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